Telix Pharmaceuticals Aktie

Thank you for standing by, and welcome to the Telix Pharmaceuticals Limited Unlocking the Potential of PSMA Therapy: A Next-Generation Portfolio. [Operator Instructions]

I would now like to hand the conference over to Mr. Stewart Holmstrom, Director of Corporate Communications. Please go ahead.

Hello, everybody. My name is Stewart Holmstrom, Director of Corporate Communications at Telix. We're very pleased to welcome you today to our educational webinar to present on unlocking the potential of PSMA therapy and Telix's next-generation portfolio approach.

We can just move to the next slide, please. I ask you to take a moment to look at our disclaimer.

Next slide, please. I'm very pleased to introduce today's speakers. Dr. David Cade, Group Chief Medical Officer at Telix, will present on Telix's PSMA targeting therapeutic portfolio. And then I'm delighted to welcome our guest speaker, Professor Louise Emmett, Director of Theranostics and Nuclear Medicine St Vincent's Hospital in Sydney, a Conjoint Professor of Medicine at the University of New South Wales and Clinical Research Leader at Garvan Institute of Medicine Research and also the principal investigator on the OPTIMAL-PSMA trial that she will present today, along with case studies and perspectives based on her experience with TLX597-Tx.

Following the presentation, Dr. Cade will take questions via the conference line and webcast Q&A function. Professor Emmett, who has been very generous with her time already whilst presenting in Europe, will be available afterwards to respond to questions via e-mail.

And with that, I'd like to hand over to David.

Next slide, please. Well, thank you, Stu. Today, together with Professor Louise Emmett, who is one of the globally recognized pioneers in the development of radiopharmaceutical therapies for prostate cancer, I'm hoping that we'll be able to enable you to gain from our discussion a useful understanding of 3 important themes. And the first of those is we'll briefly discuss the current first-generation small molecule radioligand therapies and where in the treatment cascade, they've established themselves for advanced prostate cancer.

Secondly, we'll also discuss some of the challenges that have emerged in applying first-generation small molecule agents earlier in prostate cancer where patients tend to be fitter and healthier, and why Telix is taking a portfolio approach based on very distinct mechanisms of action with TLX591, which is a radio antibody drug conjugate being developed for advanced metastatic castrate-resistant prostate cancer in the ongoing Phase III ProstACT Global trial.

And with TLX591, which we haven't really talked a lot about previously. This is a highly targeted second-generation small molecule radioligand, which has demonstrated a favorable dosimetry profile with a very minimal salivary gland and kidney dose, but a very high tumor dose, which really makes it uniquely positioned for use in earlier metastatic hormone-sensitive prostate cancer.

And then thirdly, I'm looking forward to Professor Emmett, who will discuss her St. Vincent's Sydney group's rapidly growing experience with TLX597, which Professor Emmett and her team are studying in the OPTIMAL-PSMA randomized Phase II trial, which Professor Emmett presented very recently at the IPCS Congress in Lugano in Switzerland.

So if you go to the next slide, please. So I think this slide really very nicely summarizes on the left-hand side there, how we would typically treat prostate cancer once it's broken free from the prostate gland and it's become metastatic. And what you can see is that for early metastatic hormone-sensitive prostate cancer at the start of the disease journey, we would typically use androgen deprivation therapy to block testosterone and/or would use the newer androgen receptor pathway inhibitors or we may use a taxane chemotherapy, especially if the patient has high-volume metastatic disease.

But then what invariably happens is the prostate cancer learns how to progress despite the testosterone tap having been turned off, which is what we call metastatic castrate-resistant prostate cancer, we see that PSMA-617, which is Novartis' agent Pluvicto, is appropriately established for advanced metastatic castrate-resistant cancer over on the right. And this was established 3 or 4 years ago when the VISION trial showed a 4-month extension in overall survival with PSMA-617 when compared to conventional standard of care.

And from here, of course, a very logical next development of such an agent is to undertake trials in earlier disease settings, which is what the PSMAddition trial sought to do. But what PSMAddition also showed is that there are emerging concerns when we try to treat earlier, healthier patients. And the 2 main concerns really could be summarized as the radiation dose to the salivary glands that tends to lead to dry mouth that then degrades patients' quality of life as well as the radiation dose to the kidneys, which may lead to long-term kidney injury.

So in other words, we're probably overtreating these patients with a first-generation radioligand therapy, whereas what we really need is a second-generation agent that exhibits a very low dose to any of the normal tissues if we're truly going to be able to deploy radioligand therapy widely in early mHSPC.

So if you go to the next slide, I think this really does nicely summarize those points that were made at the ESMO Congress in Berlin last October, where Dr. Tagawa from Weill Cornell, he presented the interim data from PSMA addition and Dr. Azad from Peter MacCallum in Melbourne was the discussant, and he critically discussed the results from PSMA addition and the take-home messages that we in the audience should take away for our clinical practice.

And -- what he concluded were really 4 key take-home messages. The first of those was the PSMA addition is the first randomized Phase III trial demonstrating efficacy of radioligand therapy in mHSPC. And ultimately, the progression-free survival benefit will probably lead to regulatory approval in multiple jurisdictions. But to date, there's been no improvement in overall survival really shown. And to date, lower quality of life has been exhibited with PSMA-617 in this disease setting. So that's a very important point.

Secondly, he reminded us as we sometimes forget that he reminded us that the goal of any cancer treatment is to make patients not just live longer, but also live better, and the discussions view was that this was not achieved in PSMA addition.

Thirdly, he indicated that he wouldn't currently recommend the widespread use of PSMA-617 in mHSPC at this stage. And the final point he made, which is very, very important, was that to deliver the best outcomes in mHSPC, it's going to take a really patient-centric approach focused on avoiding overtreatment while minimizing the impact on quality of life and minimizing those late toxicities.

So if you go to the next slide, please. And so if we took all that we've learned from the last few years' experience gained with first-generation small molecules and say we were to draw up a wish list, if you will, of those characteristics that a second-generation radioligand therapy would need to succeed. These can be summarized, I think, very simply. So firstly, we would absolutely demand a very low radiation dose to that organ that's responsible for clearing the radioactive drug from the body, which for small molecules is typically the kidney or we prefer the clearance organ to be the liver, which is an organ that is actually quite forgiving of radiation delivered to it.

Secondly, we also demand a very low radiation dose to the exocrine glands, primarily the salivary and the T glands.

Thirdly, would also demand a higher and more prolonged tumor retention. Especially given the relatively short retention time that characterizes first-generation agents.

And then fourthly, we want to be able to apply a very patient-centered approach with both dose intensification, which is dialing up the amount of activity that we administer and adaptive dosing, which is administering only when the patient needs it to simultaneously improve both disease control and quality of life, which Professor Emmett is going to discuss -- she's going to discuss these concepts in a bit more detail shortly.

And then finally, we'd ask for compatibility with alpha isotopes like actinium and lead.

Next slide, please. And so with those attributes in mind, let's now move to TLX597 or Lu-DOTA-HYNIC-panPSMA to give it its full name. And what was evident right from the very early Phase I trial that was done by Professor Omar's group was that TLX597 is a highly targeted small molecule agent with a dosimetry profile that exhibits a minimal kidney and salivary gland dose while achieving some very significant PSMA -- PSA reductions in heavily pretreated patients. And you can see this in these 2 patients from Professor Omar study on the left-hand side there that he reported at the European Nuclear Medicine meeting just late last year.

Now today, Professor Emmett's more recent randomized Phase II trial known as OPTIMAL-PSMA, that's about to complete patient enrollment has further demonstrated the very highly targeted behavior of TLX597, again, with really minimal uptake in the kidneys and the salivary glands, while in Professor Emmett study, additionally confirming very high radiation dose being delivered to the tumors, which is exactly what we want.

Now if you think about these properties a little more deeply, they uniquely position the TLX597 agent for the important developmental objectives of, number one, dose intensification and adaptive dosing, which Professor Emmett is going to talk about shortly as well as use in earlier metastatic hormone-sensitive prostate cancer, and Professor Emmett will discuss this concept in a bit more detail as well.

Next slide, please. So I think this is my last slide. And I think it really is articulate in its simplicity. And while I won't spend too much time here, this summarizes our drug development intentions across the continuum of prostate cancer care based on very distinct mechanisms of action that are tailored to both the disease state itself as well as the condition of the patient.

And the way I would summarize it is TLX591, which employs the radio antibody drug conjugate mechanism of action, utilizes an antibody targeting vector to deliver that therapeutic payload, which enables long tumor retention with limited radiation to the healthy organs as we would want and that the short 2-dose regimen with 2 fractions, 2 weeks apart is primarily intended to allow this agent to be combined with the other standard of care agents that the patients is also going to be receiving in the mCRP setting. And that's the intent of ProstACT Global that many in the audience would be familiar with.

Whereas on the other hand, there's a very significant opportunity in mHSPC for TLX597 due to its potentially best-in-class dosimetry profile that makes it uniquely suitable for earlier use in mHSPC as well as the dose intensification to achieve those further efficacy gains.

So hopefully, that sets the scene nicely and clearly. And I think it's time I pass the mic to Professor Emmett, who's going to discuss some of the ground -- what I believe to be really groundbreaking work that she and her group has been doing at St. Vincent here in Sydney. So with that, I'd like to pass to you, Professor Emmett.

Thanks, David. So it's a great pleasure to be here and to be able to discuss OPTIMAL-PSMA, which we've been beavering away at now for about 9 months. So just next slide.

The OPTIMAL-PSMA is a randomized Phase II trial, and it is about -- it's about dose intensification compared to standard of care dosing, and it really originated from this slight frustration, I guess, of the fact that we're dosing 6 doses, 6 weekly, most doses of 7.4 gigabecquerel, and we based that dosing on external beam dose constraints to the kidney. We haven't based it on efficacy. So we've done a number of randomized Phase III trials at the moment now where we haven't had a lot of significant kidney dose, but we struggled with overall survival. We have shorter progression-free survival than I would like to see with PSMA radioligand therapy.

And the question is, are we actually optimally dosing? So OPTIMAL-PSMA is about evaluating the dosing interval and whether we should do short intensified dosing right upfront to attack the cancer cells when they're most vulnerable. And then have maintenance or why I call it mowing the lawn a little bit later. So we're doing 6 doses on each arm over 6 weeks, but we're dose intensifying upfront in just one of the doses.

And it was very nice that we were able to really do some work on Lu-PSMA-597 before the trial started. So with safety lead in with the trial and looked at the dosimetry. Dosimetry is a big part of the trial, and we're doing a lot of translational work as well. But perhaps we can just look at the next slide and just have a look at the dosimetry.

So this is dosimetry that's been derived from the safety lead-in first 12 patients of the trial. So single injection, so first dose of these patients, they had 3 time point dosimetry with the TLX597 and just compared to previous publications of PSMA-617 and PSMA-I&T.

What we see with the dosimetry and it's been done twice. It's been done by our physicist and it's also been done formally by Ascinta Technologies. So I'm happy that these results in the nontarget organs are absolutely 100% correct. The kidney dose is 0.28 gigabecquerel, sorry, compared to 0.58 and 0.71. And then when you look in the lacrimal salivary gram, you've got significantly lower lacrimal salivary grand activity than either PSMA-617 or PSMA-I&T, but we don't have lower tumoral activity. So that's a really nice combination. Low salivary, low kidney maintained tumor, and that's really what you want to see.

Next slide. So when we look here, we've got -- on the left, we've got the 4-hour, 24-hour and 120-hour delayed imaging, SPECT after a single dose of Lu-PSMA-597, 7.5 gigabecquerels. 4-hour image, you can see a lot of background activity. You can see some low-grade salivary gland activity, not very bright, really almost struggled to see the kidneys, but quite nice bright tumoral activity. 24 hours later, tumoral activity looks a bit brighter, salivary gland activity looks a bit less bright, once again, struggling to see the kidneys because there's quite a lot of bowel exclusion with this agent. And then 120 hours, really nice bright tumor. almost can't see the salivary glands at all and definitely can't see the kidneys.

So on your right, similar time point, we're comparing this to PSMA-617, SPECT dosimetry. And you can see those salivary glands are really quite bright and they stay bright up to 160 hours following injection. Similarly with the kidneys, you can see quite bright activity within the kidneys, staying bright up to 168 hours post injection. So I do think that this is a very nice dosimetry, David. I actually think this is optimal dosimetry for a small molecule, right?

Yes. Well, I think Professor Emmett, it would be really interesting to sort of hear a little bit more about what prompted your -- I mean this is very intellectual thinking what you've set out to do in the study. It's one singular question you're aiming to answer, which is does dose intensification, which is really the constant tendering together of the first 3 fractions. So you're dosing day 1, day 3, day 15 very intensively. The underlying thesis that you formed in designing this trial was the upregulation of the PSMA target. So maybe you could talk about the data on that, the literature on that and why you thought that this approach might work.

Yes. So actually, it's the upregulation of the PSMA receptor with DNA damage is an appealing concept and there's some preclinical work on that and some work we did at St. Vincent's. But the other thing is we've got -- the radiobiologists tell us that when we hit with lutetium, it's all done and dusted within a couple of days. And there's some very nice work in lymphocytes that show that you have radiation induced foci for up to about 96 hours. But after that, it's all healed. So DNA damage repair heals at all.

And so 2 things. What I'm really interested in is if we -- instead of just giving one big dose upfront, we split it up and we give it in a time fashion to when the DNA damage is not yet healed, do we get a deeper hit by hitting already damaged cells. That's one thing.

And then Johann de Bono's lab, she and et al a couple of years ago published a very nice work that if you damage the cell -- prostate cancer cell, particularly mCRPC prostate cancer cells with radiation, you actually increase PSMA expression. And that happens in the first few days as well. And so we actually explored that last year, we presented at PSMA Theranostics Conference a series of patients where we did day 1, day 7 dosing with Lu-PSMA-I&T and 2/3 of those patients actually had increased PSMA expression.

So putting the -- wanting to hit while the cell is damaged together with wanting to have increased PSMA expression, we came up with a day 1, day 3 dosing, but then we thought Scott Tagawa has got some great outcome data of day 1, day 15. So we did day 1, day 3 and then day 15. And so obviously, that's a brave trial to be doing because we would clearly be concerned about toxicity. So we have done a series of data safety monitoring Board meetings within the trial to see whether we ran into toxicity at all. But the idea is if we can intensify dosing and time it to the radiobiology and the PSMA biology, can we actually get really, really deep responses in these patients. So next slide.

Understood.

So this is actually the trial schema. It's a randomized Phase II, as you said, it's a 2:1 dosing. So we've got 80 patients in the dose intensified arm. We've got 40 patients in the standard of care arm. Patients had to have metastatic castrate-resistant prostate cancer. They have to have failed an ARPI -- they have to have failed docetaxel or be chemo ineligible for docetaxel, but a lot of patients on this trial have actually failed 1 or 2 lines of chemotherapy that have quite high-volume disease.

And then in the first 35, 40 patients on the trial, we actually started at 7.5 gigabecquerels in the dose intensified arm. So we gave 7.5 gigabecquerels day 1, day 3 and day 15 and then 10 weekly in the experimental arm. And in the standard of care arm, it's 7.5 gigabecquerels, 6 doses, 6 weekly until no longer clinically benefiting, which is essentially standard of care.

And all patients have a PSMA PET scan. So we started off using the vision criteria with the PSMA PET scan. We actually moved to the ENZA-p criteria after the first data safety monitoring meeting. And then we do a repeat PET at 8 weeks on all patients in the trial.

For these patients given your referral patterns from both metropolitan Sydney and regional centers, what is the patient population? What prior treatments have they been exposed to given that in Sydney, Australia?

It's a mix. The vast majority of patients have had docetaxel. A significant proportion of patients have had both docetaxel and cabazitaxel. All patients have received at least one androgen receptor pathway inhibitor, all patients are metastatic castrate resistant. I think we have a very high volume of disease on the trial because we don't have much access in Australia to lutetium PSMA therapy at the moment, we've deliberately made the inclusion criteria of this trial very broad. We take very sick patients. We take super scans. We take patients who are hemoglobins of 80 and falling and we get these patients on to this trial.

So the primary endpoint, because we're looking about whether we can go deeper, whether we're going to be deeper in terms of our responses with dose intensified, the primary endpoint is PSA 90% response rate. I think that's quite a high bar in terms of primary endpoint. But we're also looking at PSA 50% response rate, PSA and radiographic progression-free survival, overall survival. And importantly, safety, quality of life and dosimetry. So we're doing multi-time point dosimetry in all the patients on the trial on both arms so that we get very good data about Lu-PSMA-597. We're going to be able to look at biologic effective dose of dose intensified dosing compared to standard of care dosing.

We've also doing ctDNA on this. So we're doing ctDNA at multiple time points, so we can look at ctDNA clearance. So we're actually clearing cancer cells from the blood using a more intensified dosing than we are with the standard of care dosing. And because Lu-PSMA-597 is so new, the standard of care gives us a great opportunity just to see how it benchmarks compared to other lutetium PSMA agents, small molecules and antibodies in terms of toxicity and effect.

I think an obvious question is, given the extent of prior treatment that these patients in this trial have received, how are they in your experience so far? And I know you've recruited very rapidly, how are they tolerating that dose intensified regimen in the experimental arm? Could you comment on that?

Yes. So it's one of the things everyone thinks you're very brave and looks at you slightly a stance that we're even thinking about doing this dose regimen. And when I first put the patients on the trial, I told them they may need blood transfusions, they were going to feel terrible. They were going to have this, they were going to have that -- it's been very interesting in terms of the toxicity. The toxicity has been very low. We did the Data Safety Monitoring Board meeting with the 8.5 gigabecquerel dose intensified in March.

And so we looked at the first 10 patients who had dose intensified Lu-PSMA-597, and that was after 10 weeks. And I think we had 5 grade -- so we had 5 grade 1 anemias. We had 2 Grade 1 thrombocythemias, we had 1 patient who had grade 1 xerostomia and 2 grade 3 lymphopenia. So it is well tolerated. I will say that with the dose intensification in patients who have very high-volume disease, we do make pain worse in the first couple of weeks. So they get a really big response to this dose intensification at their sites of disease.

We do have to make sure they have a pain plan, and we do put them on dexamethasone for the first couple of weeks just to reduce the fatigue that they might feel as well. That's actually a treatment response effect. So get a bit of pain around the time of lutetium, that's a good sign. No pain is not a good sign. So -- and then their pain is great. They're coming off their opiates. They're feeling very good.

What I really want from this -- so they're great. We're not having any problems on this trial, but what I really want to know is can we make it last longer as well?

Yes. Yes. Understood.

Next slide. So this is just a couple of the early patients. And it's one of the things that just showing what's happening between the day 1 and the day 3 dosing in these patients, and it's pretty uniform. So when we did the first injection, you can see here, it says dose 1, day 1 on the far left, the SUV max the salivary gland was 11, SUV mean 9.4 of the tumor. And this patient got metastatic disease in bone in their mid-thoracic spine, and they've got a series of lymph nodes in their paraaortic region that you can see there.

And then if you go to dose 2, day 3, so this is the SPECT images taken after the second injection, day 3. You can see the salivary gland looks a lot less bright, right? So it's gone not as bright and the SUV max is 5. And then -- but the tumoral intensity has actually gone up. So the SUV mean and the tumor has gone up to 14, the SUV max has gone from 51 up to 124. So we're getting increasing intensity in the tumor, and we're getting reduced intensity in the salivary gland.

And if you look at the next patient, you can see the same thing. So salivary gland activity, dose 1 day 1, SUV max 5.2, dose 2, day 3, it's gone down to 1.8, you almost can't see it at all. So it's super, super interesting that you are reducing salivary gland activity while increasing tumoral activity.

And in this second patient with very high-volume disease, you can see the SUV mean's gone from 5.7 to 7.9, SUV max gone from 25 to 74 and the tumoral volume has gone from 2,379 ml to 3,977 ml. So whatever the mechanism, we're getting a lot more lutetium into those cells with the day 3 dosing.

The question is whether we're getting more dose into those cells than we would dosing them week 1, week 6. And that's one of the big questions of the trial really.

And would you say that -- I mean, this is -- I don't know if you can answer this question, but would you say that there is a correlation between the low radiation dose imparted to the normal tissues that you don't want to hit and the tolerability, the tolerability safety profile of what you've seen? Or can you not come to that conclusion yet?

I don't think -- we'll do all 120 patients and draw that conclusion. We're giving -- we're giving 25.5 gigabecquerels in 2 weeks. And in that data Safety Monitoring Board meeting, we had 1 patient with Grade 1 xerostomia. So I'm super happy with that. I don't know whether that's because we're saturating. There's a different mechanism of uptake in salivary glands to tumor. We know that. And it looks to me like this dosing regimen is saturating the salivary glands, but it's not saturating the tumoral activity day 1, day 3.

So we know if we gave cold PSMA and then gave an injection of lutetium PSMA, we would have reduction in salivary glands and we'd also have reduction in tumor. But perhaps the regeneration of the PSMA expression in tumor is so fast that we've still got saturation in salivary glands in day 3, but we've actually overcome the saturation that we might have had with the injection by day 3 in the tumor, and we've got increased expression in -- either in relation to DNA damage or because we're overlying dose and we've got persistent activity because this agent has got really nice persistence in the tumor cell. Either way, I don't care. It's looking really bright. I can see we're getting a really nice deep radiation dose to all of those sites of disease where we want it, and we're not getting it where we don't want it. So I'm happy with that. That was -- that's cool. Those images are really cool for me.

I like the images, too. Yes, thank you.

Next slide. So this is just one of the patients on the study, and these are 4 our SPECT images actually underestimating the volume of disease of these patients. This is a patient who's pretty classic for us post chemotherapy post 2 lines, obviously, post-op because that's an inclusion criteria, very high-volume disease. PSA is 1,380, hemoglobin 112, platelets 200. So what we have here is the day 1, day 3, day 15 dosing. And these are the SPECT images that are all taken 4 hours after each injection, and then we have the week 10 dosing.

So you can see that in this patient, the day 1 dosing, high-volume disease, day 3, it looks -- the volume has gone up again. Day 15, you get the impression it's not as bright. There's things going down. And then by week 10, there's a marked reduction in the number of sites involved. So a marked reduction in the volume. And you can see PSA has gone from 1,380, day 3 has actually gone up, and that's something that we routinely see. Pretty mixed at day 15, sometimes it's up, sometimes it's down, but down to 40 by week 10. So really nice PSA response there correlating with the really nice SPECT imaging response that we see at the week 10 dosing. And very nice to me the hemoglobin is maintaining itself and the platelets are maintaining themselves. So we're not getting a lot of -- we're not getting extreme hematotoxicity at all in these patients.

Yes. It'd be interesting. I'll ask you at the end, but your view as you go through your view on where the behavior of this peptide small molecule lends itself to future development because you're going to touch on that with earlier use. So back to you.

Yes. So next slide. Yes. I think we're almost there. I mean I -- so the OPTIMAL-PSMA trial is a randomized Phase II. We're at -- I think we are randomized -- we possibly -- I think we randomized the 90th patient today out of 120. We are getting another site on board, but that's essentially 90 patients at a single site at St. Vincent's Theranostics department in Sydney. As you're saying, David, a lot of these patients are rural. They come from all over the place to receive this treatment. So it's wonderful that we've been able to help them with this trial and that they've tolerated it well enough. A lot of patients are getting to the end of treatment. So they're getting all 6 doses, which is also fantastic. The median number of doses in therapy was 4, and that's because patients progressed around that time. About 45% of patients have progressed by dose 3 in the therapy trial. And so to me, that's the thing to be keep them on trial longer and see how long we can keep them on trial, how long we can keep them alive and feeling well.

Yes. Yes. Well, as I talked about earlier in the intro, Professor or Dr. Azad, a colleague of yours from across the border in Victoria down to [ indiscernible ] made that very thoughtful discussion session of PSMA addition and talked about some of the requirements for an agent for metastatic hormone-sensitive prostate cancer. I think it would be very interesting to get your thoughts on the development in that disease setting and your OPTIMAL-E trial that you've already, I think, got IRB approval for.

We do. So I think one of the reasons why we had the baseline PSMA PET and then the week 8 PSMA PET was we're thinking with the intensified dosing, we might be able to stop treatment in some of these patients. And we do, do treatment pauses frequently with -- so they continue the ADT, but they pause treatment with lutetium PSMA until they get first confirmed right, most patients who have a marked reduction in PSA and volume on their SPECT or their PET images.

We haven't -- we've had very high-grade aggressive disease in the patients here. A number of these patients are actually super scans. So we've had good deep responses, I believe. But we haven't paused treatment in any of the patients in mCRPC. But I think in mHSPC, you have much better behaved clonal populations. You have more sensitive disease. It's a combination. It's always combinations that you use. So PSMAddition is ARPI, so androgen receptor pathway inhibitors plus ADT plus lutetium PSMA. And we showed in the ENZA-p trial that if you use 2 effective agents together, your responses are massively deep. Our PSA 90% response rate in mCRPC in ENZA-p was 95%.

So if you're using ARPI plus ADT plus lutetium very early, you're going to get extremely deep responses and a lot of patients will have no disease left. If you just keep treating them, then you're going to end up getting a higher dose to the non-target organs. So I think Lu-PSMA-597 does lend itself well to the earlier space. It's got low salivary gland, low kidney activity. We haven't seen a lot of hematotoxicity yet. But of course, we have to read out the whole of OPTIMAL-PSMA. And so it does lend itself to going earlier. But I think it also this idea of adaptive dosing in the hormone-sensitive space where you treat upfront, then if you lose the target, you stop, you continue the very active ARPI and ADT regimen. And then at first confirmed PSA, you retreat again.

So next slide. I think we've got the OPTIMAL-E concept. So this is OPTIMAL-E. This is the version of OPTIMAL-PSMA accepted in the metastatic hormone sensitive space for patients who've got metastatic disease at diagnosis. You can tell it's designed by a nuclear medicine physician because it's dust full of imaging. And we really want to see what's happening to that target as we go. So there's a screening PET to make sure they've actually got disease. And then the patient goes on ARPI, so an androgen receptor pathway inhibitor, either enzalutamide or abiraterone or darolutamide. And then at day 8 after commencing the ARPI, they have a PSMA PET. And then we commence day 1 and day 3. So we do a dose intensification, 8.5 gigabecquerels of those patients on the trial. We do a 6-week dose. We do a 12-week PET -- and then if there is no residual disease on the 12-week PET with the lutetium PSMA ARPI and ADT on board, we stopped the LU-PSMA-597. So ARPI and ADT would continue until first confirmed PSA rise and then we would start administering again.

If there is residual disease, then we give another 2 doses of Lu-PSMA-597 at week 14 and week 22, and the patient has another opportunity at 6 months, so week 24 to see whether there's -- whether all disease has gone on the SPECT as well as the PSA -- around the PET as well as the PSA. And if it hasn't, they get another 2 doses. So this is what we call adaptive dosing. We're trying to treat when the target is present stop if it's not present and then recommence again the minute target starts to come back. And we look at target coming back based on PSA rise.

So the question is how long can we go in some of these patients with very well-behaved disease with a dose intensification upfront with the lutetium PSMA and then stopping if they've got well-behaved disease. Is it years? I hope -- I really hope that, that's years before that clonal population comes back. In the ENZA-p trial, which we did a similar thing, we did a PSMA PET so that we could start and stop treatment, some of those patients only got 2 doses, and it's 6 years now, and they still have no measurable disease. So can we treat multiclonally and actually eliminate whole clonal populations for these patients, potentially cure.

Yes. So in your mind, what would you want to see? Obviously, OPTIMAL-E in metastatic hormone-sensitive prostate cancer is really the first proof of concept with dose intensification and dose adaptation so that we don't overtreat blindly a patient that negatively impact the quality of life. What would you want to see from such a study if you were to say, right, based on achieving this outcome, this warrants a registration enabling pivotal trial in this early disease setting?

Okay. So I hope we get a number of patients with reasonably high-volume M1 disease in this small study. I hope that we see that the ARPI and the ADT and the lutetium PSMA are working extremely well together with the dose intensification such that when we get to week 12, 3 months, I'm hoping we have a very high proportion of patients who have a PSA of less than 0.2 and nothing left on the PSMA PET. A lot of the benchmarks for overall survival in mHSPC is around the week 24 mark with a PSA of less than 0.2.

What proportion of patients can we get to that? So if you're just ARPI and ADT and you are using and you're not using lutetium PSMA, that's about 68% of patients you would expect to have a PSA of less than 0.2 at 6 months.

What proportion can we get to without inducing a lot of toxicity just by dose intensifying upfront and then giving patients an opportunity to de-intensify their treatment and go back to the ARPI and the ADT again. And then how does our quality of life compare, say, to 6 doses upfront. There are other trials that are doing this. [ MPP ] has got a very interesting design. It's using -- it's giving baseline, it's giving day 1, day 7, 7.4 gigabecquerels of Lu-PSMA-617 with ARPI and ADT. And then 6 weeks later, it's giving day 1, day 7 again and 6 weeks after that, it's giving another day 1, day 7.

So dose intensification is happening at day 1, day 7, not day 1, day 3. So I think they're beyond the window of the DNA damage. And then they don't have the adaptive dosing design. And I think the adaptive dosing design is something that patients want -- they will want that. And I do want to know whether it works. Certainly, in the studies that we've done in the castrate-resistant setting, we've see no disadvantage to stopping treatment with losing the PSMA target. Patients feel well. They're not coming in for continued treatment. They don't have the associated toxicity. They don't get the very dry mouth. Potentially, we're avoiding renal toxicity, and then we're treating when they really need it when the PSA starts to rise again and the clone is on the move.

Yes. That's very clear.

I think it's interesting. We've got different ways of doing it. But if we got to week 24, all of our patients had a PSA of less than 0.2 or 95% of them had a PSA of less than 0.2 and 70% of them have been able to stop treatment because they didn't have anything left on their PSMA PET. I think that would be amazing. We'll see.

Yes. You say that would be your benchmark for saying, right, it's pivotal trial time. Yes. Understood.

Well, that's my benchmark. Obviously, other people will have different benchmarks, but I would be pretty happy with that.

Yes, very clear. Very clear. Okay.

I just want to say one thing, David. And that is we're so grateful to do this trial. Our OPTIMAL-PSMA has provided treatment access to many men across New South Wales in Australia. They are very grateful. I'm grateful that Telix has provided this access to this drug. It's been fantastic. But I just want to shout out to my team. Putting 90 patients on as a single site with a randomized Phase II trial has been heroic, and I really want to say thank you to them.

No. I think Professor Emmett, that's a critically important point. I've never seen a single center trial enroll at the rate that you've been able to do. So you and team and your patients are truly something out of the ordinary. Thank you.

Next slide.

Okay. So look, on behalf of those who have dialed in to the webinar, I'd really like to thank Professor Emmett, who's, I think, evidently doing some of the most evolved thinking in prostate theranostics at the current time. These are concepts that take a lot of CTU cycles in an academic brain. And I think we're seeing that a lot of thinking is going into this, Professor Emmett.

So I hope today's discussion has gone some way to look, clearly articulating Telix's portfolio approach based on 2 very distinct mechanisms of action, TLX591 in metastatic castrate-resistant prostate cancer, but now TLX597, which is exhibiting some best-in-class small molecule distribution and dosimetry and tolerability characteristics that we believe make it really uniquely suitable for achieving the requirements for metastatic hormone-sensitive prostate cancer that was so well articulated at ESMO last year, i.e., that the goal -- number one, the goal of any anticancer treatment is to make patients live longer and live better. One without the other is not sufficient. And i.e. that to deliver the best outcome in metastatic hormone-sensitive prostate cancer. It's going to take a really patient-centered approach, which Professor Emmett has really, I think, driven home about not overtreating and adaptive dosing, focused on avoiding overtreatment, focused on minimizing the impact on quality of life and focused on minimizing late toxicities.

So with that, I'd like to thank you, and I'll pass back to the operator, and we'd be very happy to take any questions from the audience.

[Operator Instructions] Your first question today comes from David Dai from UBS.

So just on the safety, it looks like dosimetry of bone marrow is correlated to tumor lesion, whereas patients without extensive bone lesions have limited dosimetry of bone marrow. So based on this data, how should we think about the potential hematological toxicity for TLX597, especially in early line hormone-sensitive prostate cancer patients?

Yes. Thanks, David. Great question. I think as you've seen, Professor Emmett presented the preliminary dosimetry, and she was at pains to explain that, that was in the first 12 patients that were enrolled to the trial. Ongoing dosimetry work is being done. But it's very clear that the dosimetry is at a multiple PSMA-617. It's a multiple of that agent in the tumor lesions and it's a percentage or it's a fraction of relative to that agent in the nontumor compartment. And that's the salivary glands, that's the kidneys and that's the bone marrow.

So Professor Emmett has not extensively reported on the bone marrow dose, but it is similar to the kidney and salivary glands, very, very low. And that's why the hematological toxicity with small molecules as a class of drugs, but in particular, with this second-generation agent, the bone marrow dose is also very, very low. And that's what's correlating with the low clinical expression of hematological toxicity. So it's a very consistent profile, David, across the tumor compartment and the non-target normal tissue compartment, whether it's salivary gland, kidney or bone marrow. Does that answer the question?

Yes, that's really helpful. And so maybe just kind of follow on the dosimetry. So I just want to kind of follow a little bit more. Just based on the SPECT biodistribution data, it looks like there is some dosimetry in GI. So maybe just talk a little bit more around what do you think potential GI tox look like, especially the constipation or diarrhea and vomiting that we're seeing Pluvicto. Do you expect this to be replicated in PLX-591 as well or 597 as well?

Well, we don't, no. And the reason we don't is that this is a -- we are developing -- just to be clear, we're developing a new radiopharmaceutical. It is not in any way a generic version of Pluvicto. So it's a new -- it's got a new structure to it. It's basically being designed with a different linkage to Pluvicto and PSMA-I&T and the other small molecule agents that fundamentally alters its chemical and its physiological properties. Unfortunately, I can't really disclose more than that, but those altered chemical and physiological properties govern its biodistribution, which is essentially where it goes. And ultimately, where it goes governs the dosimetry, the radiation absorbed dose that it physically imparts.

And so all of the off-target or off-tumor tissues are touched by this asset very, very minimally, and that includes the GI tract as well. So the adverse event profile that Professor Emmett has observed in her 90 patients that she reports to her independent data monitoring committee have had very low constitutional side effects, fatigue, nausea, vomiting relative to the other small molecules.

Your next question comes from Andy Hsieh from William Blair.

Thanks for answering a very important perhaps long overdue clinical question about dose intensity and optimization. So I have a question about the patient enrollment criteria. I think for the OPTIMAL-PSMA, the enrollment criteria was VISION and then transition to more ENZA-p. And so maybe for the first part, I'm wondering if you could talk about why ENZA-p enrollment criteria is enriching patients who will be likely candidates for intensification.. AND also the rationale for the OPTIMAL-E, it seems like it went back to the VISION study. So maybe kind of the rationale behind that enrollment criteria.

And then maybe a quick one -- so for docetaxel -- sorry, not docetaxel, for dexamethasone usage, I believe that dexamethasone also reduces PSA. So I guess when you look at the PSA reduction down the road, I'm curious how you would interpret the data delineating between the 597 contribution also the dexamethasone contribution.

Yes, Andy, basically characteristically solid question from you. So the first question, just to restate it is you asked about in Professor Amit's current on foot OPTIMAL-PSMA trial, which is enrolling 120 patients is the target, and she's done, she's enrolled 90 of the 120. During the trial, she increased the PSMA positivity criteria where she started with the VISION criteria and she tightened the criteria to the ENZA-p criteria, which is a study that she was the principal investigator on.

Now the primary reason she did that was that these patients in Australia are very late stage, so metastatic castrate-resistant prostate cancer, very heavily pretreated, and they have failed or sorry, progressed while on or become intolerant to all of the conventional therapies, which is primarily and taxane chemotherapy, mostly cabazitaxel and docetaxel.

So these patients are very heavily pretreated. And what Professor Emmett wanted to do was to evaluate in this trial whether she could -- she started with a dose intensified regimen. She wanted to further dose intensify, which she did during the trial with the permission of IRB. She went from 7.5 to 8.5 gigabecquerels. So she inject -- she is now injecting a much higher amount of activity at each injection and she's constant tendering the first 3 injections together, if you will, on day 1, day 3, day 15.

So that's a very dose intensified regimen. And what she wanted to do was make sure that with that heavily dose intensified regimen and in the population of heavily pretreated patients that she was making sure that they were highly PSMA positive before they're enrolled as a means of making sure that they were appropriate patients. So that's why she's done that.

In terms of what this OPTIMAL-PSMA trial has shown. It has shown that this molecule is -- it really facilitates 3 objectives. Number one is dose intensification and dose adaptation, which is only treating when the target is present and not overtreating when it's not present. Number two, this has shown that the off-target deposition in the normal tissues uniquely lends itself to the metastatic hormone sensitive prostate cancer setting, which is what this trial OPTIMAL-E will evaluate. And then thirdly, if you think more over the horizon, it lends itself to use with an alpha isotope again, because of the low deposition in the kidney in particular. So that slide Professor Emmett has already planned and got approval for OPTIMAL-E, which is the study she talked about, Phase II trial in 20 patients that is combining this agent with conventional androgen deprivation therapy and ARPI.

Now I can't really comment on really the role of steroid -- concurrent steroid. But she will look at the 4 ARPIs. She'll start with darolutamide and enzalutamide and then expand this trial to apalutamide and abiraterone. So all 4 will be studied and then we'll be able to answer that question once those data are in hand. So it's a detailed answer to a very thoughtful detailed question, but I hope that addresses it, Andy.

I think we've got time for a couple more questions. We've got about 2 or 3 minutes to go.

Your next question comes from Melissa Benson from Barrenjoey.

I just wanted to kind of step back and understand, I guess, the rationale a little bit more about the 2-product strategy. If it is kind of focused and it seems like it's based on this reduced salivary uptake, low renal clearance, those are kind of both attributes of 591, obviously, because of its antibody in nature. So trying to understand, is it perhaps that the heme tox profile is less acceptable in kind of earlier stage hormone-sensitive disease and that's kind of part of the rationale. But also, is there anything that -- I remember you had the prostate TARGET trial with 591, which was kind of in that earlier like a BCR setting, but some of those patients are effectively hormone sensitive. Is there anything you learned in that, that's kind of guided this need for kind of a 2-product bifurcation?

Yes. Thanks, Melissa. And I think it's -- that's an important question, but it warrants a thoughtful answer. And I think the key point is that we at Telix fundamentally focused on the patient and a focus on the patient requires a focus across the entire disease journey or spectrum. And you can see that in the prior composition of the therapeutic portfolio for prostate cancer. It includes TLX591, but it also includes the development of TLX592, which is actinium, an alpha therapy, which must follow lutetium, it can't go ahead of lutetium. And then after alpha, an agent for bone pain, which is a sort of a prepalliative stage of the disease journey.

So we have -- we continue to develop 591. It's uniquely positioned as a radio antibody drug conjugate for metastatic castrate-resistant prostate cancer. And I think we've its unique virtues in a very detailed kind of way. It's the long tumor retention, it's the prolonged radiation dose deposition and the fact that it is able to be given as a 2 fraction, 2-week apart dosing regimen really lends itself to be intercalated or combined with conventional standard of care that a patient is going to get. So we're asking the question, can we layer on top of standard of care a radio antibody drug conjugate.

From there, though, we have looked upstream to mHSPC. And we have really thought deeply about the findings of PSMAddition, and we have been thinking about this for a long time. And we don't believe that just treating blindly with 6 fractions when the target life disappear is in the best interest of the patient. So we believe that in that early disease setting, a mandatory condition is that you do not do 2 things. You cannot adversely affect the patient's quality of life by having significant off-target effects. And secondly, you cannot injure critical organs like the kidney and have long-term toxicities because these patients, we are aiming to help them live a long time, measured in years. So we cannot be allowing them to live for years, but with renal injury and potentially renal dialysis as a consequence.

So that's why it requires a very patient-centric approach and a fundamental rule in medicine is to do no harm, first of all, do no harm. So that's why we think an asset like this is intended for metastatic hormone-sensitive prostate cancer in that early metastatic setting. That's what I would want if I was a patient.

So I hope that makes sense, but that's our view of the world. And I think it's a very thoughtful view of the world. And I think you can hear the sort of ambition that Professor Emmett hands in taking this upstream to where she's currently studying it.

I hope that answers the question. I think we're probably at time. But if there -- I just apologize if there's any other questions that we haven't been able to get to. We would be very happy to have those triage to our Investor Relations team. And Professor Emmett was at pains to say she'd be delighted to respond to any questions. It's 2:00 a.m. in Europe at the moment. So we can't ask her to do it right now, of course. But within sort of the next day or 2, she'll be very keen to respond.

So I'll hand back to the operator with that. Thank you to the audience for dialing in, and thanks for your attention.

Thank you. That does conclude our conference for today. Thank you for participating. You may now disconnect.

Thank you for joining us today. I'm Robert Burns, the Managing Director and Senior Biotech Analyst at H.C. Wainwright. I'm joined today by Chris Behrenbruch, the CEO of Telix; and David Cade, the CMO of Telix. Gentlemen, thank you for joining us today.

Thanks very much. Good to see you, Robbie.

Awesome. So why don't we just dive in?

For those who may be unfamiliar with Telix, can you give us a brief overview of the company and give us a recap of your 2025 earnings that led to a strong year-over-year growth as well as the disease areas that you're focused on?

Yes. Thanks. So we're a fully vertically integrated radiopharma company specializing in oncology. We have a portfolio of focus in urologic oncology and neuro-oncology in particular. We are a commercial stage company. This past year, we did just over $800 million in sales, primarily around our U.S. prostate cancer imaging franchise. That's our -- we have two approved FDA-approved products in that space and very active product portfolio on the therapy trials, which I'm sure we'll get to at some point as well.

But in terms of commercial performance, we've just put out our guidance for 2026, targeting the mid-900s in revenue. And really reflective of, I think, a very solid growth in the prostate cancer imaging space globally, but particularly the U.S. as well as the launch of our second prostate cancer product, which got passed through in October of last year. So that's putting a fair bit of momentum into our commercial operations as well. So I'll pause there. Hopefully, that's a good snapshot.

Yes. No, it definitely was. I sort of wanted to hone in a little more on the revenue guidance that you provided. So I know it's around $950 million to $970 million in revenue for 2026, with roughly a 25% growth in the Precision Medicine business unit. When we think about the growth opportunities for the PSMA franchise, where do you see significant upside for that agent as well as the new launches in brain and kidney cancer, specifically Pixclara and Zircaix.

Well, our guidance doesn't include any unapproved products. So it's -- so when we get approval for Pixclara, which we've just resubmitted just this past week and Zircaix is not too far behind. As you recall, we had a CRL for both of those programs last year. Then we will revise our guidance accordingly. We still expect to resubmit Zircaix obviously this year and hopefully launch it this year as well. That product has a breakthrough designation. So pending the review of the CMC issues we had with the FDA. We expect to get that program back on track. For the prostate cancer area, I would say there's sort of three drivers for the business. First of all, there is the inherent growth still in PSMA. We think that's 5% to 7% a year based on the fact that there's still white spaces in the market. There's still referral urologists that are getting up to speed on the value of PSMA. It may surprise you to know it. But CTs and bone scans are still prescribed and obviously, practice of medicine has changed.

And maybe David can elucidate a little bit more how that practice is changing. We also see urologists taking more and more of a front line interest in PSMA imaging. So we're seeing -- I think in the steady state, call it, 3 to 5 years out, you're going to see 25% to 30% of the market for PSMA imaging actually directly controlled by urology. I think that's an emerging sort of category of PET scan or user/owner/stakeholder.

And I think the second tailwind on the PSMA landscape is really around having a second product that's got passed through. Gozellix is a very innovative product. It offers some real clinical and distribution benefits. And by having a product segmentation strategy or market segmentation strategy for prostate cancer. We really target commercial and hops payers very differently. And I think that gives us a commercial advantage that will translate into revenue.

And then I think the third one is we have a significant Phase III trial running this year, which is the BiPASS biopsy study. This is an opportunity to significantly grow the TAM, the BiPASS study stands on the shoulders obviously, of great work that's been done in academia, particularly the PRIMARY2 study that was recently presented. We actually wanted to take that study to the FDA -- actually took that study to the FDA for -- sorry?

We lost you for a second there.

I'm really sorry. Can you hear me now?

Yes.

Well, let's continue. I'll continue for a second, and then we'll just pause and do an audio catch-up. But basically, the PRIMARY2 study, we actually took that study to the FDA, and it does require some tweaks for it to be a label indicating study. So -- but there's a very important education process that's going on in the process of executing that study. And I think that builds further momentum into where prostate cancer imaging can be used. So I'll pause there. Hopefully, you've got some of that. But yes, there's a lot of -- there's a lot to look forward to in prostate cancer imaging in '26.

So one of the things I'm curious about is if the BiPASS study actually succeeds, what does that mean for the market expansion potentially in terms of the number of scans that you might be eligible to garner?

Yes. Dave, why don't you have a chat about the clinical consequence and maybe what that means in TAM.

Yes, sure. Robbie, it's a very important question, and it was really brought to us by our clinicians themselves. Essentially in the United States, we just focused on the U.S., there's north of 1 million biopsies done for the -- to try to establish the diagnosis of prostate cancer a year. And I emphasize the word try because a very significant proportion of those somewhere between 750,000, maybe 800,000 of those don't yield tissue that can be decisively ruled by a histopathologist either being prostate cancer. So the yield from the biopsy is low.

And as a consequence, there's a very significant number, maybe 250,000 men that actually decline a prostate biopsy when they probably should. So there's a lot to improve. Now the way it's usually done is with an MRI scan. And I won't bore you with all the details, but the MRI scan is scoreboard according to a 5-point scan, which is called the PI-RADS system, 1, 2, 3, 4, 5 where 1 is a very normal scan. Typically, we don't get a lot of PI-RADS 1s in the men that we -- in the age group that we expect to have prostate cancer. That's like a very normal scan. PI-RADS 5 is prostate cancer. So there's an area in the middle PI-RADS 2, 3 and 4, particularly PI-RADS 2 and 3, which is a very significant group where the MRI is unresolved. It doesn't indicate to the urologist where to biopsy from.

So we typically end up doing what we call a template biopsy, which is sort of a row 4, 4, 4, 4, 4 so basically somewhere between 12 and 20, maybe 12 and 24 needle cores for the biopsy, and even yet it doesn't yield the results. So what there is a huge opportunity to do and the results of this study in this BiPASS study are already showing us is that with the Gallium PSMA PET scan added to the MRI it can either direct using that imaging where the biopsy should be taken. So instead of doing 24 core biopsies. It can be image-guided and 1 needle core can be taken.

Or on the other hand, if the Gallium PSMA PET scan is negative, no biopsy needs to be taken at all, and the patient can be reassured and put on to active surveillance where their PSAs monitored and they come back and are simply non-invasively scanned at a later date, 6 or 12 months' time. So for lay people, and this is not a lay audience, but for the lay people, I explain it this the one and done or none and done, which is a major deescalation of what we typically do today, which is very unsatisfying with that low yield of diagnosis. So you can see with that utility that opportunity is very significant, as Chris described, and that's probably an explanation of why this BiPASS trial is enrolling so rapidly, possibly even ahead of plan, which, as you know, doesn't happen with trials all that often.

Yes. So just to summarize, we're talking about sort of an estimated 750,000 to 800,000 scans with -- at the way that, that clinical evolution takes place. And then what it also does is it affords the question to be asked in the future, should PET follow MR or, in fact, should PET lead MR, and that will be something that will come out as there's more experience with clinical practice and combining the two modalities.

Yes. At least for me, as a male, it seems like I would definitely prefer to have the added on diagnostic imaging rather than having to take these numerous core biopsy samples, which are frankly onerous.

Yes. Well, and also it's just a cost. I think it's a cost issue. I mean if you look at the health economics of replacing biopsy, not just the cost of biopsy and the practice demands but also the morbidity issues associated with it. It's going to clearly save the health care money -- health care system money. And as you know, it does patients care about this. And in fact, it's hard to know the exact number, of course, because it's an estimate, and literature varies fairly widely.

But there's estimated to be 200,000 to 250,000 men that simply don't participate in the process because just don't want stuff near their nether regions. And if we can -- I'm putting that as diplomatically as I can. And so I think that if we can make patient compliance better and patient engagement better, that's going to have a big consequence on detection rates. So I think it's very positive.

I would certainly agree with you that -- why don't we move on to your therapeutics pipeline now? So you recently reported initial data from Part 1 of the ProstACT Global trial, which is our Phase III trial, mCRPC. Can you provide an overview of that trial design? And remind us what you reported in terms of safety as well as dosimetry and what impact that has on Part 2?

Sure. Look, when we took the protocol to regulators, not all regulators had the same viewpoint on it. We had a number of sophisticated regulators that were quite okay based on the data that we had of going straight into ProstACT Global, which is a randomized Phase III trial across 3 different treatment cohort. So it's a standard of care plus versus a standard of care alone randomized study. The 3 different treatment arms are enzalutamide, abiraterone and docetaxel combinations. And we've selected those because those RP switches and taxane reflect sort of consistent global standard practice in first and second-line metastatic prostate cancer. When we went to the agency, they felt that we were a little bit light on the combos with the RPs comparatively. And we went in with a view that enzalutamide and abiraterone are a class, and we had some data to support that assertion, but the FDA wanted to see a bit more.

And that's where the genesis of the Part 1 study came out. So it's really to reinforce that there's no particular delta between the different treatment arms, particularly the RPs. I mean we had some combination data with docetaxel. We showed that it was tolerable in combination with docetaxel, but we had -- we were a bit lighter on than the FDA wanted with the RPs. And so that's why we've done this additional study. We've, as you know, just put the results out. Maybe I'll make an initial comment, and then David, if you want to chime on anything. But the purpose of the study, as you know, was safety and dosimetry. We were really looking on a cross-cohort basis. There's always been a lot of speculation around the asset, around safety and particularly hematologic AEs. And what we hope that the data shows sort of fairly definitively is that these are well-tolerated treatments.

The 591 layers very nicely on top of those different combinations. What the data shows is that we do have hematologic toxicities. It's the main toxicity associated with it, but it's transient and self-limiting and reverses very rapidly even when the adverse event is a higher grade adverse event. And that's counterbalanced by the fact that the patient-centric AEs are very benign because we don't have salivary gland, exocrine gland uptake. We don't have renal excretion. And so we think on the balance that it represents a very compelling risk benefit. That's what's demonstrated in the safety data. And now we'll be taking that combined with the dosimetry, which is, again, very favorable, particularly compared to current solutions that are in routine clinical use. We'll take that to the agency with the expectation that we'll be able to move to Part 2 and dose patients into Part 2 in the United States in the fairly near future.

Awesome. One of the things I'm sort of curious about as well, what are the next steps in terms of opening up enrollment within the U.S.

Yes. So I mean we did recruit patients in Part 1 in the U.S. So we do have sites that are sort of in the program. We will, of course, be adding a bunch more that are particularly focused on the Part 2. It is a global study. So we have regulatory approval, I think, now in 7 or 8 countries. We are actively recruiting patients in Canada, Australia and New Zealand. We've got U.K. just coming online. So we are rolling out the program globally. I expect that we'll get U.S. patients subject, of course, to what the agency says into the study around midyear, maybe early Q3.

We expect about 20% of the study to be recruited in the U.S. And yes, obviously, it's critically important to get U.S. patient experience for the study. So yes, it's a high-priority study. We're really pleased with the data. I think it sort of finally benchmarks once and for all the profile of the drug. And unfortunately, when we deal with targeted radiation, cytopenias are a common side effect, but the fact that the management of those AEs are so straightforward that was the clinical experience gives us a pretty clear platform for discussion with the agency. I don't know, David, do you want to add anything just from a medical perspective?

Yes. We took a lot of patient input into the design of the trial, a lot of FDA input into the design of the trial. I think fundamentally, the Part 1 results do demonstrate the feasibility of integrating TLX511 with a contemporary backbone of different global standards of care as mentioned, just what the prevailing practice in the United States, which is predominantly RP Switch, but also outside of the United States, both Europe and in Asia, which is primarily moving from an RP to docetaxel.

So it really is, as the name of the study says a global trial. So we would see -- should the trial meet its primary endpoint, it would lead to simultaneous filings, not just in the United States and Europe, but ultimately Japan, China, South Korea and so forth. So that's why we designed it that way. I think it's a very pragmatic trial. And as Chris mentioned, the next step is to take those data. They're exactly what the FDA asked for, and we'll take it back and present it to the FDA seeking an IND amendment to start to put U.S. patients into Part 2, which is already enrolling elsewhere.

So talking about Part 2 of the trial, what is the sort of enrollment trend that you're currently seeing for that portion of the trial?

Yes. I mean I can initially comment. So the trial is certainly picking up steam compared to the Part 1 study. The Part 1 study took a long time because it was a very technical study. It required a lot of SPECT Imaging, a lot of patient visits. So we had limited it to -- because of its technically demanding nature, we had limited to a number -- limited number of sites. Now we've added, of course, a lot more sites for the Part 2. And so that's a natural accelerator. Also, the protocol in Part 2 is just much more streamlined. There's a single time point PET imaging for patient selection. It's much more like a clinical treatment protocol for conventional PSMA RLT therapy. So we do expect to see a pickup. And obviously, having some data out as well from Part 1 is quite motivating, I think, for investigators to kind of get on with the study with a sort of clear understanding of what they're dealing with and how they manage patients going forward. So we've seen good pickup.

The goal this year is we have based on an event-driven process, obviously, on 25% of events, so around 80 patients. We expect to report out a futility, an interim futility. We've discussed that with a number of regulators, but particularly with the FDA. We don't have -- obviously, because it is event-driven, we don't know when that's exactly going to drop, but we would imagine sometime around Q4 or Q1 next year. And that will be the next sort of milestone on the study as far as the Part 2 randomization goes.

Well, I'm certainly looking forward to that data. One of the other questions I also have, I note that you also have TLX592, which is -- which utilizes an alpha emitter versus the beta for 591. How are you thinking about the sequencing of those 2 agents within your portfolio and the treatment paradigm specifically?

Yes. Look, we're exploring a number of things on alpha. We haven't locked down finally what our PSMA strategy is really going to be in alpha. 592 is a fairly very early-stage asset. We have done some human studies with 592, but they were done with PET imaging as a surrogate. As you know, actinium is quite tough to image in humans. It can be done, but it's not sort of that straightforward. So what we did is we did targeting and biodistribution studies with PET -- with copper 64 as a surrogate, not that we have the intention to develop it commercially, but to get a sense in a benign way of really what the pharmacology of that agent is like, and that looks quite promising. So we are getting ready now to do the first-in-human actinium studies with that agent. We're starting off in very late-stage patients that have typically progressed on lutetium therapy. So that's where we'll get initial clinical experience with that. But the value proposition of 592 is really twofold.

First of all, it doesn't have exocrine gland uptake. So one of the real challenges with small molecule delivery of alphas has been salivary and lacrimal gland ablation and not typically transient, usually fairly -- well, more serious, I would say, in terms of grade than what we typically see with a beta emitter. And then secondly, we've had discontinuations of programs recently for renal toxicity with renally excreted alphas. Again, that will vary from program to program. But generally speaking, alphas don't have much business ending up in your kidneys. The liver is a far more radio-resistant organ. And so the attraction of 592, it's somewhat derived from 591, hence, the sort of naming convention is that it is also hepatically excreted like 591. It has very little renal excretion.

And so the expectation is that it's a better suited moiety for targeting alpha emitters. And I guess we'll find that out in due course. We, of course, we dabble in small molecules. I mean we want to understand the field. We have a fairly active R&D program looking at alpha emitters with small molecules as well because, of course, the advantage with smaller formats, and we look at small molecules, we look at small proteins. We have a protein engineering team in Los Angeles that looks at smaller formats. Of course, the advantage is that as we move into earlier lines of therapy, and I think the sweet spot for alpha is honestly not treating late-stage advanced bulky cancers. It's not really what the radiobiology of alpha is optimal for.

I think if we -- I think alpha will have its sweet spot one day in targeting that very low burden of disease in the early metastatic, perhaps even hormone-sensitive space, that's where alphas will be fantastic. And then tumor penetration is really going to matter. But also those patients are going to live for a very, very long time. And so we've got to be confident that when we're parking an alpha emitter, particularly with respect to clearance organ that we are not creating something that's going to be a major downstream multiyear risk for the patient. And I think that's where the field has quite a bit of evolution to still undertake.

Yes. When you think about the alpha emitter space, obviously, you have actinium as well as 212PB or lead. There are a few players within the lead space. Obviously, ARTBIO is one of them, advanced cell prospective therapeutics. How are you thinking about the utilization of lead specifically with the small molecule components?

I mean, look, there is a sort of a heuristic in radiopharma that your pharmacologic half-life and your radio biological half-life should sort of somehow be similar. Of course, we also ignore that heuristic quite often. I mean lutetium PSMA products that are out there today in commercial use or even in late development are obviously violate that. You have a small molecule that has some hours of resonance time and then you put lutetium on it, which has a multi-day half-life. So we're obviously -- we're not very dogmatic about it in practical reality. I think that the challenge with the short half-life alpha emitters is really when you're dealing typically with a small molecule, you're dealing with something that's under the threshold of first pass renal clearance. You have to manage the design of your molecule very carefully around kidney metabolism.

And if your alphas end up in sort of prolonged glomerular retention, you're not going to really have a great outcome for the patient. And so you want those decay events to happen quickly with a small molecule because typically, it's not targeting a lesion for very long before it gets washed out. But on the other hand, you also want to make sure that those events are not taking place in your kidney. So we've had -- we've seen in the last few months, we've seen discontinuations of programs because that balance between imparted energy to the tumor and excretion is not really balanced.

No, I completely agree with you there. When we think about the mCRPC space more broadly, obviously, there are a few other modalities that are targeting PSMA. T cell engagers are a great example of that. We've seen data from GenX as well as Amgen. How are you thinking about the deployment or physician preference for a radiotherapy over a T cell engager...

Yes. I think it's a really important question. And I sometimes feel that the nuclear medicine community, we sort of ignore these questions at our peril. So part of the answer to that is how we've tackled 591, which is really -- because it's a short duration of treatment, it's much more appealing for a medical oncologist to refer a patient. They're not handing over a patient to an authorized prescriber in nuclear medicine or radiation oncology for 40 weeks of therapy, right? So it's more -- and in fact, if you look at the global design, what we're trying to do is really layer 591 on top of kind of routine standard of care so that the patient management dynamic sort of status quo.

And we've seen nuclear medicine products fail in the past because there hasn't been parking clinical efficacy aside, there hasn't been adequate motivation for a referral physician to just hand over a patient to another specialty. So I think that is particularly in the U.S. context, I think that is a real kind of just practical challenge. And yes, we forget, and you're quite right to raise it, we forget kind of ignorantly that MedOnc has a lot of opportunities to prescribe innovative new drugs to patients. There's a lot coming down the pathway. You made a couple of great examples. We're seeing next-generation androgens. We're seeing PARPs. We're seeing all kinds of other things impact standard of care in prostate cancer.

And I think that the short answer to your question is really that radiation is incredibly valuable as a pillar of therapy of durable treatment response in metastatic prostate cancer. And you have to think about radiopharmaceuticals as the sort of migration from a box from traditional linac-based approaches to systemic approaches, but it's really the evolution of radiation oncology. And I think that managing prostate cancer, as we all know, it's about therapeutic drugs, it's about surgery and it's about radiation. And so I think that PSMA-targeted radiopharmaceuticals have a very natural role alongside potentially other immunomodulatory strategies in prostate cancer. So I think they're actually complementary. We see radiation as a driver of immune response in all kinds of cancers. We haven't seen a lot of success stories on the immunology front in prostate cancer so far on the immuno-oncology. And so I actually think that radiation can drive more success in this space. But yes, there's a lot to think about as the field evolves.

No, I completely agree with you there. Thank you for those insights. Why don't we shift gears now to TLX101, which is currently being evaluated in the IPAX-BrIGHT study, which is a Phase III trial in brain cancer. Can you talk a little bit about how that trial is designed, what the status of it is as well as the market opportunity there?

Dave, do you want to talk about IPAX-BrIGHT, more your wheelhouse?

Yes, sure. Maybe I'll open, Chris, and you can add some comments. But Robbie, IPAX-BrIGHT, as you said, it's a Phase III trial of our Iodine-131 amino acid asset, which is relevant because you need a small molecule to cross the blood-brain barrier. This asset targets the LAT1 large amino acid transporter, which is expressed in glioma tumors. We've got a number of studies that are sort of precedent studies, IPAX-1, IPAX-2, IPAX-Linz, which is an investigator-initiated trial that have demonstrated meaningful tumor control and some extended survival.

So I'd caveat that because these are Phase I trials, but survivals from time of diagnosis in the range of 23 to 32 months. So these are meaningful survivals given the median survival is typically the order of 9 to maybe 15 months in that population. Essentially, IPAX-BrIGHT is our Phase III trial. And this study, again, has a Part 1 and Part 2. I won't bore you with all of the detail, Robbie, but Part 1 is a Bayesian design, which aims to optimize the dose of TLX101 and to optimize the dose of Lomustine, which will be the control arm. So there's 2 agents and the FDA requires us and other sponsors to spend a fair bit of time at the front optimizing the dose magnitude and the dose schedule. So that's part 1, optimizing the dose of 101 together with Lomustine and there's a Bayesian design that does that. Once we get to the optimized dose, there will be an expansion cohort.

Then we get to the exciting bit, and it's a familiar theme, Part 1 and Part 2 of ProstACT Global, we talked about but IPAX-BrIGHT has a similar schema where Part 2 is a randomized Phase III design where we will randomize patients to the conventional therapy, which is typically Lomustine, that's in the guidelines like NCCN guidelines versus Lomustine, again, which is having 101 layered on top. So the question that is being asked in this trial is can we take a conventional standard of care and add a radioligand therapy on top of that to improve upon the standard of care. And in this setting, it will be overall survival. These patients have a limited duration upon recurrence. This population is patients with recurrent glioblastoma and overall survival is the primary endpoint of this trial.

Can I just make a quick time. We are...

Please.

We've been getting monotherapy data, IPAX-BrIGHT. IPAX-2 study was monotherapy data. We have done a dose escalation study, just to be clear. So we have an idea of what we're targeting in terms of dosing regimen. It's -- as David noted, it's about layering that now on top of standard of care where the extra run-in piece is required. So when we've done prior studies, including quite a bit of compassionate use experience in Europe, patients have typically been receiving whatever standard of care is available, whether it's Temozolomide, Lomustine, adjuvant radiation therapy, additional surgical. I mean it's been the whole heterogeneous hail Mary of recurrent glio research or clinical management. But now it's really about locking that down into a slightly more constrained study. And so that's really what that run-in part of BrIGHT. It's not about to validate dosing because we've done that, but it's about really ensuring that the dosing assumptions that we have on top of standard of care -- on top of a prescribed standard of care hold up as we go into Phase III.

So I have to say Dave's team has done a phenomenal job from a KOL engagement perspective. We've got a bunch of sites in Europe now that have been working with the asset for a long time. I've done a lot of patients, had a really positive temperament towards the asset have seen really good disease control and treatment responses even in some cases, which we don't see in this patient population very often. So it's a very gratifying to have so much investigator momentum and interest in the study from top-tier European neuro-oncology sites is very gratifying. And we're really looking forward to rolling this out to U.S. patients this year as well.

One of the interesting assets that I also find fascinating in your pipeline is CLX250, which is being evaluating clear cell renal cell carcinoma. I'm curious where that -- what's the status of that trial that's ongoing? And from an early standard activation perspective specifically?

Yes. I'll make a few comments and then Dave, perhaps you chime in. I have to tell you this program has been very challenging because of the constant change in standard of care. I mean, kidney cancer moves so fast. And it's actually really gratifying. If you take a step back and look at the field overall, we've made huge strides in kidney cancer over the last decade. It's become a very immunotherapy-centric study. We are seeing new combination therapies evolve that are providing fairly incremental, but steadily in the right direction, survival benefit for patients. And I think the 2 cornerstones today as we see it evolve is really the immunotherapy combinations, whether that includes or doesn't include things like TKIs or cabozantinib or whatever.

And then on the other end of the spectrum, we've obviously seen the emergence of belzutifan in the last-line setting. And so what this has done is we've been developing our sort of Phase II strategy around this asset. We've been taking multiple approaches. We've been looking at combo immunotherapies in first and second-line setting and how to layer in kind of more traditional treatments. And we continue to do research in that area. But what we have decided is that there still remains an unmet need in last line rapidly progressing patients. We don't feel that, I mean, belzutifan has emerged as a new standard of care in that setting, but it's not. I don't think it's -- I don't think anyone believes that it's a very overwhelming solution. And so I think whilst it's good to have a new option in that patient setting, and there are a lot of patients that progress off immunotherapies, I think we can do better.

What we learned from this initial work that we did in the space is that we can resensitize patients back to immunotherapy to an extent with radiation. And we have some fairly compelling monotherapy data. And so what we have done is we've gone back and said we're going to do a, call it, a VISION trial style study in last-line progressing metastatic patients and then start to work upstream in parallel with the immunotherapy combination. So we have, for example, a study that's open at the moment, that's combining immunotherapy checkpoint inhibitors with targeted radiation that's being run at MD Anderson.

So we have these sorts of studies, which are really about preempting and planning a little bit what happens when we move upstream from that monotherapy advanced metastatic signal. So that's the current plan today. That's what the LUTEON trial is designed to do. It's to really -- to look at that last line setting where there really isn't a lot of treatment options. It's a traditional place for nuclear medicine to be. And then once we get that monotherapy efficacy confirmation because we have some pretty nice data that shows disease modification and stabilization in that patient population, progression-free survival, prolongation, then there's an opportunity to move up into the earlier lines with combination immunotherapy. Dave, do you want to add anything?

Yes. Thanks, Chris. Robbie, you'd be familiar with this, but I just want to highlight the need. There are -- we've had a major advance with immunotherapies over the last decade. And those patients who enjoy a response, that's great for them, but it's only -- it's a 30%, maybe 40% of the population that you expose to an immunotherapy agent in advanced kidney cancer that get a response. So there's a large group that when I talk to patients about this, they often say things like what if I blow through and just go straight through because I'm not one of the responders. And they're the ones that are really worried about needing something else. So there is a large subset that end up in the treatment refractory end of the journey very quickly. And that's why we need assets like this to be developed and...

And also why we need the imaging as well. And just the same way as we're seeing PSMA playing a huge role in patient selection and longitudinal patient response assessment in prostate cancer, we already see the same demand for renal cancer. There's no doubt that the Zircaix product, which we still expect to launch this year -- that's the true companion imaging agent to 250. It's actually the same targeting agent. It's actually, we are able to do predictive dosimetry with the zirconium agent for the lutetium product, which is really exciting. That's the first time that we've had that in our portfolio because, as you know, prostate cancer imaging has really centered around small molecule imaging. But with renal cancer, particularly for primary staging, we want to keep the ureters nice and clear. We don't want bladder. We don't want kidney. We don't want anything. Basically, from the belly button downwards, we don't want any -- we don't want to see any of that.

And so that's why a hepatically excreted agent very compelling for imaging. But ultimately, that asset is not going to get just used for indeterminate renal masses and primary staging and maybe evaluation of reoccurrence. But ultimately, it's going to get used for looking at treatment response. and to try to determine, as David says, when is the patient really truly progressing and to try to get ahead of that and not subject the patient to prolonged toxicity from immunotherapy if there's something that -- or cabozantinib or belzutifan, if there's something that you can do if you can move them on more quickly and still preserve some capacity to respond.

Thank you for that. One of the things I'm also sort of curious about because I know we're running up on time, so I'm going to make this succinct. When we think 5 years down the road, 5, 10 years for Telix into the earlier-stage pipeline, how are you envisioning the mixture of validated targets versus more novel nuanced targets as well as beta versus alpha emitters? And what do you think is the most underappreciated aspect of Telix?

Well, that's all of us underappreciated our current market cap. I think we're trading at a poultry multiple of our commercial business, but I think you'd be disappointed if the CEO didn't say that. So I'm just meeting my obligations there. But I think at the end of the day, look, I'll be the first to admit. Some of our portfolio has fairly well-trodden targets like everybody does, but we think we're taking a differentiated approach from a pharmacophore perspective. Our focus on biologics is quite unusual, mostly because biologics are harder. But the selectivity and the engineering that you get on a protein gives you all kinds of strategies for PK modification and changing your biodistribution.

And so it is more complicated. It takes longer, but it also gives you a lot of really great control and flexibility over where you steer radiation. And I think one of the things when you look at Telix's pipeline, whether you like our targets or you don't like our targets or whatever, is we choose the right radionuclide for the biological problem that we're trying to solve. And I think that, that's really important. So we do have the appetite to say, all right, this is the cancer biology we're dealing with. This is the radiobiological mechanism of action we're hoping to achieve. And here's how we're going to steer it within time and energy constraints, this is how we're going to steer that radioactivity to that -- with that particular goal in mind.

Now we are -- as you noted before, we are -- we do work in Lead-212. We do work in actinium. We do work in astatine. If you want to get something across an intact blood-brain barrier, chelators and radio metals are pretty challenging. charge matters. Pretty tough to do, but radiohalogens have lots of potential. So we have, for example, a near-term first-in-human study with an astatinated amino acid, which is for looking at leptomeningeal disease. That's a really beautiful example of where you have a widely disseminated -- relatively small metastases. It could be a great opportunity for an alpha emitter, but you still need to have things that have a more favorable CNS biodistribution. So you need to think about your radio labeling strategy there as well.

So those are the sorts of thoughts that we have as we develop the earlier-stage pipeline. Some of our first-generation products were either small molecules that people relatively well understand or antibodies, full-length antibodies. I think that the sweet spot somewhere in the middle where we're dealing with smaller formats potentially that have better tissue penetration, but are still steerable to more radiation-resistant clearance organs. Internalization still matters even with alpha emitters, receptor-mediated internalization is different than binding to the substrate of a receptor and having some transient on-off effect. So I think there's a long way to go. I think what we really see now is the first generation of pharmacophores, and we've been -- we've had some great successes for the field, but there's a lot more that we can do to optimize the pharmacology of radiopharmaceuticals for the types of isotopes that we're interested in delivering to patients.

So I think that's the science lens of the company. And fortunately, we're in a great position where through some M&A and through some organic investment, we've been able to build new capacity. And in fact, this year, you will see the beginning of a couple of very novel targeting agents, including with novel targets that will come out and go into first-in-human studies where you'll see the fruits of that labor materialize.

Well, I'm definitely looking forward to all of the innovative science and data that's going to be coming out of Telix, both this year and in the future. Gentlemen, thank you for taking the time to have this insightful discussion with me today.

Yes. Thanks. I'm sorry about the audio. I hope it came through reasonably well, but I always appreciate the opportunity, and you always ask great questions, Robert. So thank you.

Awesome. Take it easy, Chris. Nice to see you again, David.

Thanks, Robert. All right. Bye-bye.

Good morning, everybody. My name is Kyahn Williamson, SVP of Investor Relations and Corporate Communications at Telix. And we're very pleased to welcome you today to our investor call and webcast to present the results of the ProstACT Global Phase III study, Part 1 safety and dosimetry lead-in.

I'm just looking to the next slide, just ask you to take a moment to have a look at our disclaimer.

In terms of -- and then moving to the next slide. Very pleased to introduce today's speakers. Dr. Christian Behrenbruch, our Managing Director and Group CEO, will make some brief introductory remarks. Our Chief Medical Officer, Dr. David Cade, will present the data. And then I'm very pleased to welcome our guest speaker, Dr. Pedro Barata, Medical Oncologist with the University Hospitals Seidman Cancer Center and Associate Professor of Medicine at Case Western Reserve University School of Medicine in Cleveland, U.S.A. and also a ProstACT Global Steering Committee member and investigator on the trial to also share some case studies and his perspectives.

Following the presentation of the data, we will open the call up to questions from analysts. These -- through the conference call line, these will be focused on the clinical data. For the questions that we don't get to or questions on the webcast, we will respond to you at the conclusion of the call if we can't get to your question. With that, I'd like to hand over to Chris.

Thanks very much, Ky. I'm going to actually hand over to my clinical colleagues in relatively short order, but I would like to make a few brief introductory comments. We are delighted to present the results of the ProstACT Global Phase III study Part 1, and we thank for your patience as we closed out the study and completed the data and dosimetric analysis in preparation for engagement with the FDA.

As a reminder, this Part 1 study is a specific requirement of the FDA in order to proceed to Part 2 in the United States.

ProstACT GLOBAL is a highly innovative trial that is designed to integrate with current standard of care in the castrate-resistant metastatic prostate cancer setting, including in combination with androgen deprivation or RP switch. RP switch is the preferred standard of care in this patient setting in the United States. However, the study design also reflects the fact that in many parts of the world, patients still receive chemotherapy following treatment with an initial RP, largely due to its cost effectiveness. As such, both approaches are permitted in the study.

The data that is presented today confirms the safety profile of TLX591-Tx in the combination therapy setting. And while an important milestone for investors is not an entirely unexpected outcome given that we had an independent data safety review committee grant clearance last year to progress to Part 2 randomization in the ex-U.S. jurisdictions where we already have regulatory approval to proceed.

Having now formally closed and read out the study, this enables us to go back to the FDA to obtain an IND amendment to include American patients in Part 2, subject, of course, to agency approval. As a reminder of the purpose of this gating study from the FDA perspective, the agency is looking for us to demonstrate safety, dosimetry and feasibility of the combination therapy and particularly the comparison between the different RP combos. As you will see, the data indicates that TLX591-Tx can be integrated with standard of care, both RP and taxane with no observed drug-drug interactions and no new or unexpected safety signals. Drug is well tolerated on top of standard of care in all 3 treatment arms. Additionally, and this is very important, based on the adverse event profile and specifically recovery from treatment-related AEs, there would be no impediment to patients receiving further treatment upon progression, including, if required, taxanes.

We're now focused on enrolling Part 2 of the study globally as quickly as possible. Part 2 has quite a different recruitment cadence in Part 1 due to the more streamlined nature of the second part of the study. It is our belief that in the not-too-distant future, combining TLX591-Tx with standard of care in the first- and second-line metastatic setting, will give physicians new options to treat patients and potentially better outcomes after failing first-line therapy.

Finally, before we move to the specific study outcomes, I want to acknowledge with gratitude the patients, their families and our clinical collaborators that continue to support this important trial. I'd like to especially acknowledge one of our key investigators, Dr. Barata, who joins us today as a speaker alongside Dr. David Cade, our Chief Medical Officer. And with that, I will hand over to the clinical team to go into the detail of the study outcomes. David, over to you.

Thank you, Chris. If we go to the next slide, today, together with Dr. Barata, I'm going to take you through the outcomes from Part 1 of our Phase III ProstACT Global study, in which we set out to evaluate the safety and the dosimetry of our lead prostate cancer therapy agent, TLX591 in combination with the androgen receptor pathway inhibitor agents, either abiraterone or enzalutamide or the chemotherapy agent docetaxel, which we evaluated in 3 separate cohorts of patients.

In essence, really all of the Part 1 study objectives comprising the safety of the 3 combinations, very clear pharmacokinetics and a favorable dosimetry were achieved. Specifically, I'm delighted to see that there are no new safety signals that were identified, and the hematologic or the blood events were both transient and manageable as we'll go through a little bit more detail later in the discussion.

The tolerability -- the tolerability of TLX591 plus RV or docetaxel given sequentially following TLX591 was supported by the dosimetry and the low grade of non-hematologic events. The lesion dosimetry demonstrated very meaningful uptake in the lesions, and there were no significant differences in the absorbed dose profiles across the 3 cohorts of patients that we studied. And then finally, there were no adverse drug interactions observed in any of the TLX591 combinations. So if you put this together, fundamentally, these Part 1 results demonstrate the feasibility of integrating TLX591 with contemporary backbone standards of care globally is a feasible approach to undertake.

So if we go to the next slide, as a brief recap of Telix's therapeutic candidate, TLX591, is a highly differentiated PSMA-targeted radiopharmaceutical that employs a monoclonal antibody to very selectively target prostate cancer-expressed PSMA while avoiding the PSMA that is natively expressed on some of the normal tissues. And what this does is it enables a very precise delivery to the cancer tissue, which is where we wanted to go of that radioactive payload. Now this approach really addresses a number of clinical needs that we need to address, particularly a 2-dose 15-day schedule that enables a much more feasible integration with standard of care, either RP or chemotherapy agents that we otherwise want to continue to offer patients. A very low radiation dose is imparted to the salivary glands and the kidneys, which are the 2 main organs that may be injured when we use small molecule agents as well as a very transient and manageable hematologic profile that we'll get into a bit more detail later on. There's very specific internalization and thus a prolonged retention within the prostate cancer cell, which is clearly evident on some of the post-treatment imaging, which Dr. Barata will show a number of case studies on. And then finally, there are some really potential real-world advantages from the lower administered activity at lower radiation doses being directed at the normal tissues, particularly in the kidneys, which may, in future, enable the patient to have additional forms of radiation therapy if necessary.

So if we go to the next slide, this slide really nicely illustrates the fundamental differences between TLX591, which is a radio antibody drug conjugate, and a first-generation small molecule radioligand therapy, for example, Pluvicto. And I think the key takeaway here is that the dosing schedule is markedly different with TLX591 being dosed as 2 fractions 2 weeks apart compared to up to 6 fractions every 6 weeks with the small molecule. And so what this means is that the total amount of radioactivity that has to be delivered to a patient is much less with TLX591. And this is because the antibody delivery vector is specifically immunoreactive with the tumor-expressed PSMA type following, which it internalizes into the tumor cell and maintains a prolonged retention, which the imaging shows.

All with pictures. So on the right, you can clearly see the biodistribution and the clearance of the 2 different approaches and the advantage of the radio antibody approach where the liver, which is a relatively radio-tolerant organ, is the primary clearance organ followed by the large bowel and ultimately fecal elimination.

The other image obviously shows the small molecule, on the other hand, which is primarily cleared from the blood circulation by the kidneys, which really does so welcoming the radiation, followed by the bladder, which you can see very clearly and ultimately, urinary elimination. You can also see significant off-target uptake in the salivary glands, which leads to dry mouth, which can be quite problematic, leading to a reduction in quality of life in quite a significant proportion of patients.

So if we go to the next slide, let's move on to the study design, and I'll summarize the patient population. Go to the next slide, please. Now here, you can see why we designed ProstACT Global, the study the way we did. It's a very pragmatic study design that aims to evaluate whether adding TLX591 on top of standard of care can improve progression-free survival and overall survival. And what it does, as Chris mentioned at the outset, was that it aims to accommodate the different backbones of standard of care that are most commonly used by and are familiar to oncologists either within or with outside of the United States. So specifically, this chart of the world indicates that in the United States, when a patient experiences prostate cancer progression while receiving their first RP drug, the predominant clinical practice is then to switch the patient on to a second RP drug; very, very established practice in the United States. Whereas outside of the U.S., the more common practice, and this is reflected in the clinical practice guidelines, both in Europe, such as ESMO and the EAU guidelines but also those guidelines in China and Korea and Japan and elsewhere, the prevailing practice is to switch the patients on to a chemotherapy agent. The most common one of those that's used is docetaxel.

If we go to the next slide, this is the overall design of ProstACT Global, the Phase III study and its current status, which is very nicely summarized on the top right. And as you can see, Part 1 -- sorry, Part 2, which is the randomized treatment expansion is enrolling 490 patients, and that enrollment is occurring currently in Australia and New Zealand and Canada following the independent data monitoring committee review in October of last year, but the study also now has the regulatory approvals, enabling Part 2 to commence randomization of patients in China and Japan, Korea, Singapore, Turkey and the United Kingdom. So that's underway at the moment.

Part 1, back to Part 1. So Part 1, which is now complete, was a prerequisite of the FDA that was required by the FDA before we were given permission to commence Part 2 in American patients. So we're really encouraged by the data from Part 1, and we look forward to engaging with the FDA with these data at the earliest opportunity while continuing to obviously enroll into Part 2 in those regions where the study has been approved to do that.

Now if we go to the next slide, this is a brief consult -- what we call a consult diagram that really outlines what has occurred so far in Part 1 as we've completed Part 1. And you can see that there were 57 -- starting at the top, you can see that there were 57 patients screened. 36 patients who each progressed while receiving a prior RP agent were deemed eligible, and all 36 of those eligible patients received 2 doses of TLX591 as planned according to the study protocol. Then you can see the breakout below that. 11 patients were allocated into the abiraterone cohort, 11 to the enzalutamide cohort and 14 to the docetaxel cohort. I think it's a very positive sign that there were no treatment-related deaths on study, and 32 of those 36 patients enrolled remain alive as well as 26 patients that continue on the study as of the time of the data cut back on the 12th of January.

So let's move on to what these patients look like. Next slide. These are the demographics and prior treatments of those 36 patients that we enrolled for Part 1 at baseline. And I think in summary, really nothing is especially remarkable about the demographics or baseline characteristics of the patients that were enrolled to Part 1 of the study. As you can see, the majority of patients in Part 1, almost 3/4 were receiving second-line therapy in this study, and the median age was 77 years which is somewhat older compared to other studies where the age is typically around 70. For example, in VISION, it was 71. So this is a relatively advanced group of patients.

In terms of prior treatment, most patients, just under half of them, had enzalutamide as their prior RP agent. And most patients, almost 3/4, have not had a prior taxane chemotherapy agent in the earlier metastatic castrate-sensitive setting. So when we look at some of the prognostic factors, a subset of which are on the right, the median PSA was similar to other studies and the ECOG performance status was good. So in Part 2, as we proceed to enroll and ramp up enrollment to Part 2, maybe we'd expect the age to come down slightly, but otherwise, it will be a very similar set of demographics in the second part of the study.

Next slide. So let's now look at the safety. Next slide. So the primary objective of Part 1 of ProstACT Global was obviously to assess the safety of TLX591 when either administered concurrently with standard of care, abiraterone or enzalutamide, or followed by standard of care docetaxel chemotherapy. Overall, the 3 cohorts demonstrated an acceptable safety profile with no new safety signals when compared to the prior studies, including the most recent ProstACT SELECT study. You can see in the table on the right, the most common treatment-emergent adverse events comprised fatigue and nausea and dry mouth, and almost all of these non-hematological adverse events were Grade 1 or Grade 2. In other words, they were mild with the exception of 1 patient who had a Grade 3 dizziness event.

The hematological adverse events, as we would expect, comprise Grade 3 and Grade 4 thrombocytopenia, which is a reduction in the platelet counts on the lab test, which occurred in 14% and 31% of patients, respectively, as well as Grade 3 and Grade 4 neutropenia, which is a reduction in the neutrophil count, which occurred in 22% and 25% of patients, respectively.

I think it's important to say that these hematologic events were certainly in line with the profile that we would expect for this class of radio-antibody drug conjugate, and they were transient and manageable as we'll discuss in a bit more detail on the next slide.

So next slide, please. So the question that comes up, of course, is when you have a hematological event are what happens. And as I mentioned in the prior discussion, the hematological events are the main adverse events of interest for this radio antibody drug class of therapy. Now in terms of thrombocytopenia, which is the most important of these events, as you can see here, the platelet counts were very consistent across the 3 cohorts with the near or the bottom point in the platelet count occurring very consistently at an average of 43 days, which is about 6 weeks after the first dose of TLX591. But what's most important is what happens from here. So from the nadir, you can see that the platelet counts recovered to Grade 1 or better than an average of about 15 days after the lowest point. And from there, they continued to revert back to the normal range in the majority of patients. Importantly, no patients experienced any febrile neutropenia related to TLX591, which is a relatively common adverse event that patients may characteristically experience from conventional chemotherapy. So in summary, the hematologic adverse events, which are very well characterized and understood from prior clinical studies with this agent were self-limiting and they resolved spontaneously without intervention in the majority of patients in Part 1. So this is very encouraging.

Let's move on to, next slide, please, the dosimetry. Next slide. So while safety was the primary objective of Part 1 of ProstACT Global, the main secondary endpoint was to assess the pharmacokinetics, biodistribution and the radiation dosimetry of 591 when administered concurrently with those standards of care. Overall, the 3 cohorts demonstrated a very predictable pharmacokinetic profile. And if you think about where you want the radioactivity to be, you either want it circulating in the blood pool so that it's available to be taken up by the tumors or you want it in the tumor lesions themselves or you want it in the liver as the drug is cleared from the body as we saw in those earlier images. Now the importance of these 2 graphs, and I'll explain them to you, is that the graph on the left demonstrates the blood radioactivity concentration, which, as you can see from the curves, is sustained but declining over time. In the right-hand graph, what we see is essentially the reciprocal of that, which I think very nicely demonstrates the tumor radioactivity concentration, which increases early and then is sustained over time through the antibody-specific binding, its internalization and its prolonged retention on site within the tumor. These exposure and watch kinetics were very clearly consistent across the 3 cohorts, as you can see by the oversitting of the lines, which indicates that there was no evidence of TLX591 interacting with any of the RP drugs when we co-administered those agents with TLX591.

Next slide. Now let's move on to the normal organ dosimetry. This is very important. So this is those organs that we want to keep the radiation away from. And as you can see very clearly, this part of the study confirmed that the radiation exposure to those normal organs was very low and certainly well below safety limits that have been determined from the external beam radiation and the radioligand therapy literature. And a particular note, you can see that with TLX591, there's a very low radiation dosing part to the kidneys and the salivary glands, which are the 2 normal tissues that small molecule radioligands tend to hit the hardest. And this reduces the risk of developing kidney impairment or dry mouth, each of which may very significantly impact patient quality of life, both during treatment and in the out years to come.

You can see on the right-hand side of this chart, the liver, as I highlighted earlier with the images. The liver is a very -- a relatively radio-tolerant organ. So it makes sense that this is the primary clearance organ and therefore, it receives the highest dose, which it is capable of doing. And then from there, the activity is cleared from the body via the right colon, the left colon and the rectum, which is sort of downstream of the liver and ultimately via fecal elimination.

Next slide. And then finally, Part 1 studied the lesion dosimetry, which, again, was highly consistent across the 3 cohorts of patients and it showed that following the administration of 2 doses of TLX591, 14 days apart, there were consistent and meaningful physical radiation doses imparted to the tumor target lesions across all of the main anatomical sites of disease, the 3 main ones being the skeleton, which is where prostate cancer goes, the lymph nodes and the soft tissues. I do think it's important to note that while these radiation doses are meaningful, radioantibody drugs possess a different mechanism of action compared to small molecule ligands. And as a recent dosimetry think tank at the ASCO meeting concluded, it's important to be mindful that tumor dosimetry is measured differently from trial to trial. And while it's available for go/no-go decisions in radiopharma development, we ultimately still rely on [ subjective ] clinical measures of efficacy, such as PFS and OS, which, of course, what ProstACT Global Part 2 is already underway to evaluate.

Now we are -- I would like to hand over to Dr. Barata. We're very fortunate to work with investigators of the caliber of Dr. Barata. And Dr. Barata is going to take us through a couple of typical patient cases from Part 1 of this study. So Dr. Barata, over to you.

I appreciate it very much, David. I hope you and everybody can hear me okay. Pleasure to be here with you all.

Can you show me next slide, please? So we have a couple of cases here, part of this component of the study for you today. And what we're looking at is actually our first patient case. So this case in brief kind of illustrates a 64-year-old patient known to have metastatic prostate cancer involving the lymph nodes who got treated with TLX591 in combination with abiraterone. So just for context, this patient had evidence of mCRPC, so construction-resistant disease, previously got treated with enzalutamide and ADT, and the investigator decided to choose abiraterone as standard of care along with TLX591 and end up enrolling in that cohort.

So baseline gallium PSMA PET did show disease in the lymph nodes, as you can see here on the left, including subcarinal, pera tracheal, abdominal, pelvic lymph nodes. So extensive nodal disease, if you will. He did receive a single dose 177 lutetium-0711 at approximately 27 80 mgl and then was followed by a serial PT to evaluate biodistribution. I think what we can see is here early images at 4 and 24 hours show kind of an expected distribution of the rather label antibody within the vascular compartment and also the liver, which does reflect what David presented before, that systemic circulation and hepatic clearance. Importantly, by 96 to 168 hours, we do see a clear uptick and which I think demonstrates effective targeting of those PSMA expression lesions. I think it's relevant to note the persistence in the signal even at 360, highlighting, I think, to me, the prolonged tumor retention of these antibody-based radiopharmaceutical. So I think this prolonged residence time, I guess, supports this radiation delivery to tumor sites. And I think it can reflect the potential advantage of this approach compared to small molecule, for example. I should note that this patient remains on study at 279 days at the time of data cutoff, and this was last January 12, 2026.

Thank you. Can we move on to next slide?

So I'm going to show you a little different case. This is an older patient, 83-year-old patient, also known with mCRPC, predominantly bone disease as shown in the baseline gallium PSMA PET that includes the disease in the vertebra as well as in the ribs. This patient was also previously treated with ABT and enzalutamide. And the investigator determined that the patient should receive docetaxel at standard of care following TLX591. So patient did receive TLX511, approximately 28 90 [ mg per kl, ] and again, serosity imaging in that context. So as with the previous case, we see early images there demonstrating the same type of distribution, which is, again, consistent with the pharmacokinetics and of the monoclonal antibody base radiopharmaceutical. And by 96 hours and beyond, we do see a clear localization of the radio tracer in the skeletal mets, which I think confirms the uptake of the sites of the PSMA-expressing tumor in the bone. It's also relevant one more time to note that we do see activity detected through the 360 hours, which again demonstrates this prolonged tumor retention and sustained radiation exposure. This patient also remained on study at 160 days at the time of the data cutoff, same day, January 12, 2026. And in this context, I think it's important to highlight the feasibility of sequencing TLX591 with docetaxel while maintaining effective tumor targeting and favorable biodistribution.

So 2 cases, one standard of care, abiraterone, the second standard of care docetaxel received sequentially. Both cases, patients were -- remain on study at the time of data cutoff.

Thank you. And please show me the next slide. I'll give it back to you, David, thanks so much. Happy to take questions.

All right. Thanks, Dr. Barata. Next slide, please. So let's summarize and then we'll move on to -- we're very happy to take questions.

So to summarize, Part 1 of ProstACT Global really has confirmed for us that TLX591 plus the most common standards of care has an acceptable safety profile. It's got favorable normal organ and meaningful tumor dosimetry. In particular, I think these findings were consistent across the 3 cohorts. That's a very important finding across those 3 cohorts that we studied. As expected, there were no new safety signals identified. There were no drug adverse interactions and that was shown very clearly in the behavior of the agent when it was combined with the RP agents. And a low radiation exposure to the salivary glands and to the kidneys are very important and I think attractive features of this agent, which really support and explain its tolerability amongst the patients that have received the agent, the 36 patients in Part 1 of the study. So really, we're very encouraged by these data from Part 1. I think they're sound, and we do look forward to engaging with the FDA at the earliest opportunity, while, of course, at the same time, ramping up enrollment into Part 2, which is the exciting part of the trial, the randomized treatment expansion in all of those regions where the study has already been approved.

So I'd like to thank you for dialing in. Thanks for your attention. I hope that's been informative. And we are very happy to take any questions.

Your first question comes from Andy Shah from William Blair.

So maybe a couple of just quick ones for Dr. Barata, if you don't mind. Just from a patient baseline characteristics, I noticed that the visceral metastasis rate is about 36%. Can you comment on that, whether that's kind of high compared to other prostate cancer studies like a PSMA-4 or VISION study? And also before the -- diagram, it seems like the screen failure rate is also a little bit high, about 37%. So I'm curious about what the most common reason for not meeting eligibility. And I have a quick follow-up in terms of maybe absorbed dose.

David, I'll defer to you if you want me to address the VISION question first or vice versa, I'll defer to you.

Yes, Dr. Barata, you go ahead, and I can add a little bit of color to it as well.

Of course. So thank you for your question, really relevant. And I think you're quoting several data sets, trial and real-world data regarding the prevalence of visual disease, right, which usually lands in up to 20%. So you are right, when we compare things, the number needs to be higher. But my interpretation is twofold. Number one, I think it's an advantage of this design is the ability to offer chemotherapy as part of the cohort here, which is different from other studies. What that means is this tells me that the investigators around the world were very comfortable offering this protocol because they have the option of going with chemotherapy, which is a standard of care in many parts of the world, particularly for patients with aggressive disease such as visual disease.

And the other piece is definitely the sense from investigators that if you have a positive PSMA as a tracer, even though you have visual disease, you do believe that radiopharmaceuticals play a role. So in my opinion, the higher rate than expected, it's a good thing for this particular study design because it reinforces the opportunity to run this study in the context of more or less aggressive disease. But to your point, in the context of more aggressive disease as well. So it does play relevance in both scenarios -- in a scenario of a crossover to a different RPI or the scenario of going with the chemotherapy. So a fantastic point that you raised.

Yes. Maybe, Andy, look, you've got a very sharp eye. So I'll answer the second part of your question. Just to repeat it, you asked in the -- diagram why was a significant number of patients excluded 57 screened and 36 enrolled. It's an excellent question. So primarily, that's because of the 21 patients excluded, 18 of them didn't meet the eligibility criteria. And within that 18, the vast majority were because there's a baseline independent radiology review that looks at the PSMA positivity of these patients. And so obviously, you want to have a high PSMA positivity, in other words, a high expression of the target because they are the patients that ultimately stand to benefit from therapy, whereas those patients with a low PSMA expression are very likely to respond. So we select patients quite heavily on that basis, and that's why patients that don't have high PSMA expression read out and thus excluded. Does that answer the question, Andy?

Apologies. Andy has dropped off the line. Your next question comes from Laura Sutcliffe from Citi.

Since Andy just dropped off, I might follow up to his question first. Do you envisage that initial baseline screen in any way becoming part of who is eligible for this in the future? So would you be cutting down your eligible patient population by the end of required PSMA expression level? And then I'll come back with another question.

Yes, Laura, look, that's a great question. And the answer is yes. So in the entry criteria into the study, patients have to have lesions or at least 1 lesion that has PSMA positivity that is twice the liver. So that is a requirement to enter the study. And that's for sensible reasons because PSMA positivity is sort of -- is an indicator of how much the radioligand therapy, the radioantibody drug conjugate, will go to those lesions. So if the patient has a very low PSMA positivity, there'll be much more off-target uptake and won't hit the tumor target. So that's why that is set. That was used in the VISION trial. We've increased the requirement for PSMA positivity in the study. And typically, the eligibility criteria guide the ultimate label discussion with FDA. But that's a matter for that discussion in the future.

Okay. And then my other question is just you've broken down in your presentation the dose absorption characteristics of the 3 groups, and they're quite similar, but the safety profile is not broken out by cohort. I was just wondering if you could comment on how the groups differ and in particular, any differences in Grade 3, 4 adverse event rates between the groups?

Yes. Look, they're actually very similar across the 3 groups, very, very similar. The most important adverse event is the hematological adverse events. And of those, the most important of those is the thrombocytes. And you can see that those 3 curves for the platelet decline to nadir and then recovery from nadir back to grade 1 and then beyond that, recovering back to normal. Those 3 curves, when I first saw them, I was very pleased to see that they almost sit on top of each other. So that behavior for thrombocytes, platelets, but also for neutrophils is very consistent across the cohorts, and it's the same for all of the other non-hematological toxicities as well. So Laura, that will be -- the FDA will want to see that. That will be a detailed discussion with the FDA, but they -- across all 3 cohorts, they're very, very similar.

Your next question comes from Tara Bancroft from TD Cowen.

This is Nick on for Tara. Given these data, what is your level of confidence that patients who remain on drug to experience longer RP FS than Pluvicto does in the PSMA 4 trial at 12 months? Or do you believe there is a different bar to use for ProstACT Global given the combination approach?

Yes. Look, the statistics of this study basically required 9 months versus 6 months, but that's not an assumption of efficacy, of course. That's just simply for the statistical planning for the sample size based on an assumed treatment effect. So that's the assumption for the sample size plan. Now that's not to say that's what we'll demonstrate. But obviously, there needs to be a meaningful progression-free survival and a meaningful overall survival. And that will be first gauged. So we don't have any reading on that at the moment. That will be first gauged as an exploratory endpoint from Part 1, progression-free survival and radiographic progression-free survival are exploratory endpoints. And we anticipate that they will probably be available later in the year, second half of 2026. Obviously, that's a time to event, which is guided by how the patients perform. And so longer for each patient is better, and that obviously pushes that out. The next inflection obviously, is guided by the interim analysis of futility, which is a preplanned inflection after 81 progression events. So that's where we're headed.

Your next question comes from Shane Storey from Canaccord Genuity

David, I'm going to continue just there with that statistical route, please. I anticipate that we'd probably see quite different activity and maybe effect sizes between the 3 controls in the second component of global. So just curious about how that might be handled. And maybe another way of asking that is whether any of the individual standard of care arms might themselves be powered for that primary endpoint, please?

Yes, Shane, that's a well-directed question. There's no -- there's an assumption of no significant difference in the effect size between the RPs and the sequence docetaxel. However, per the protocol design, and this is obviously up on clinical trials, there's -- these are stratification factors between whether they were elected by their investigator to have either RP or chemotherapy. That's a stratification factor, which means that both sides will be balanced. And that's how bias is dealt with. And yes, really, I think that answers the question, hopefully, Shane.

No, it does. So they're stratified first and then randomized second.

They are. Yes. So stratification balances out to make sure that there are more patients in one arm compared to the other getting chemotherapy or RP. And that's how that bias is mitigated pretty conventional sort of statistical approach.

I've got a couple more just back to this morning's data. You mentioned the, I guess, homogeneity of the safety sort of across the different cohorts. Could you speak maybe to a little bit more detail on the management of the Grade 4 hematologic events? I wondered whether in any of those situations whether transfusions and growth factors are necessary, please?

Just take myself off mute. All of those thrombocyte declines were self-limiting and resolved spontaneously. Two patients received platelets and 2 patients received red cells. But that's very, very similar to prior studies. 2 patients received platelets, 2 patients received red cells. Now that's pretty consistent as you would expect in patients receiving chemotherapy or receiving other cytotoxic agents or radiation therapy as well. So there's not really a difference in the rate at which blood products were received compared to studies.

And my last question, David, but my last question really, and I know it perhaps might go a little bit beyond the duration of interest that we're dealing with this morning. But maybe some comments on how many cycles of docetaxel those patients went on to receive after 591. I just want to kind of rule out the idea that there are any sort of serious deviation from the dosing protocol for docetaxel.

Yes, sure. And that's a relevant question, Shane. So in standard practice, when we use docetaxel, the median number of cycles that a patient with prostate advanced prostate cancer would get is typically 5 to 6 cycles. Now in this study, we're very confident that we've got enough patients receiving enough chemotherapy to take to the FDA. That's what they asked us to show. We didn't go into any detail on that because that is really a question of treatment intensity. Now treatment intensity, the number of cycles that the patient gets, is not obviously an endpoint of Part 1, and it's typically discussed, as you know, when we get into efficacy discussions. And so you will see that in the Part 2 results, but it's not an endpoint and not that relevant for Part 2. But we're very confident we've got enough data to -- on the docetaxel cohort to take to the FDA and have a meaningful discussion.

Your next question comes from Dave Stanton from Jefferies.

Just a follow-up on the previous question from Shane. So can you perhaps outline to us the next steps and potential time lines for that for FDA engagement?

Yes. Look, I'll also invite Chris to comment on that as well. But yes, look, I think these data, Dave, the data these clinical data are exactly what the FDA prescribed us to collect. We've now completed that. And it is -- I think we're overwhelmingly encouraged by these data, and we're really keen to put it in front of the FDA. Chris, I might ask you to sort of add any additional color to that, that you would like to add?

No, I don't. I mean we -- this is the first time that we've had the completed CSR from the study, which is why we've disclosed it in a timely fashion, and the team is working really hard to get the package in front of the FDA in a timely fashion. So it's a high priority to get U.S. patients into the randomized Part 2.

Understood. And perhaps just in the real world, can you talk to potential treatment options for TCP, Grade 3 or Grade 4 that a clinician might look to use and how to mitigate any -- that decline in a Grade 3 or 4 situation in the real world. Perhaps it's a question for Dr. Barata.

Maybe Dr. Barata, you'd be welcome to answer that question of Dr. David Stanton.

I appreciate that. I think I was having some trouble hearing the question to the end. I think real-world management of significant side effects. Is that what I heard or -- I'm sorry?

Particular -- in particular, Grade 3 and Grade 4 thrombocytopenia, please. How would you manage that in the real world to get patients through?

Got you. Got you. Yes. So I think what we've done in the protocol is pretty much aligned what happens in real world. So I can tell you that most of the time, unless you have below 10,000 platelets where transfusion, platelet transfusion is recommended because you can develop spontaneous bleed, numbers above 10,000 usually are the close monitoring with repeat labs on a regular basis and observation is what we tend to do. So the protocol in terms of managing and watching the numbers on a regular basis, repeat labs is what we would do in clinical practice, and that the periodosity or the schedule of those checks, lab checks vary. Some folks will do a little bit more often, others every week to every other week. So I would say the protocol gives you that flexibility. So what you're seeing here, it's really pretty much what we would have done in real world outside of clinical protocol.

I'll just add to that. It's certainly not an acute event. So we know the behavior of the platelet profile. And most patients in the study, as you can see, I think it's in that graph very clearly articulated that they get just below Grade 1. So Grade 1 is between lower limit of normal and 75,000 platelets. Patients spend a very, very short fleeting time below Grade 1 and then they recover. Almost all of them despite themselves back to Grade 1, which is sort of you're an MDI as well, but Grade 1 is obviously the safe zone. In fact, Grade 2 is quite safe as well, but they get back into the Grade 1, very safe zone very quickly by themselves. And then from there, most of them recover pretty quickly. So it's really, really predictable, and it's only the outlier patient that might need hematologic support with units of platelets or red cells. Now obviously, red cells declining is very, very common in radiation therapy and chemotherapy. Anemia is one of the most common side effects, but it's not characteristic with this agent.

Your next question comes from Melissa Benson from Barrenjoey.

The first one, just a quick one on the non-hematologic events, just the dry mouth or Grade 1. Should we think of that as really attributed just to the ARPI combination contribution?

Look, as I mentioned, all of the Grade, all of the dry mouth events were Grade 1, Grade 2, in other words, mild. They were very short duration as well. Now attribution is performed by the investigator. All of the attribution for dry mouth was not attributed to TLX591. So it was not attributed to TLX591. The occurrence of it has not been specifically attributed in the study. So just the investigator basically says that it's not attributed. So I guess the encouraging thing is that, yes, none of the patients had Grade 3 or Grade 4 dry mouth and none of the patients had Grade 3 or Grade 4 dry mouth that was permanent, which it characteristically is with small molecules, always Grade 1, always Grade 2 and always thinking.

Great. And just one further. You've spoken to FDA next steps. Later last year, you mentioned that you need to file a CTA with the European regulators to kind of open Europe sites. I guess just help us understand, I guess, next steps there. Are you kind of waiting first to FDA and then you'll file with Europe or that's kind of a parallel process?

Yes. Thanks, Melissa. Yes, FDA was the regulator that said we want to see Part 1 done and bring it back to show us, and we'll have that discussion for an IND amendment. European regulators did not specifically ask for that. But of course, the regulatory authorities in Europe and the United States communicate. In fact, all global regulators communicate on a regular basis. So when the European authorities saw that the FDA wanted Part 1 completed, the European agencies also wanted to take that approach as well. So now that we've got it, it will be going to the European authorities seeking permission very similar to the FDA's approach to open the study to Part 2 in the European sites.

Your next question comes from David Bailey from Morgan Stanley.

Just the SELECT trial was RP only and in this one, you've added docetaxel. So it's a broad question. You've kind of answered it already. But how would you expect adding docetaxel to impact the hematologic events? And is there anything from a data perspective between ProstACT Global and SELECT that you think might be explained by adding docetaxel into the treatment arms?

Yes. Good question. David, in Part 1 of the study, docetaxel is not given concurrently, as you know, docetaxel is nominated by the clinician, and it's started after 591, typically within a 10-week window. After 591, second dose has been given. Now there are patients that have had many cycles of docetaxel in this study. There are patients that have had the sort of median number of cycles and so forth. And as I said earlier, we've got enough to -- we believe we've got enough of that data to take to the FDA and have a very meaningful discussion.

A lot of patients don't -- when they're feeling great after a therapy, they don't want to start docetaxel. So a lot of patients will actually decline it. I would like to invite Dr. Barata to maybe comment on how his patients view docetaxel versus RP and their willingness to start it. Maybe Dr. Barata, you could comment on that.

Right? That's a fantastic question and a fantastic point, David, that you raised. So I think it's common -- it's known to all of us that patients don't love chemo, right? They're looking for nonchemotherapy options. Perhaps that's one of the reasons why there's so much ARPI switch is done at least in the United States, where we can actually do it.

So from that perspective, when you give a therapy that works and you're doing well on it, you would expect or you will expect some pushback from patients and quite honestly, also from providers, right, because they don't feel as strongly regarding bringing the chemo right now as per protocol is defined versus upon progression. It's almost like you're buying time, you have tumor control. So the more you have an active agent, that provides you tumor control, evident in scans, PSA, patients doing well. Actually, I would argue, it would not be residual. The amount of patients who say, you know what, give me a break, I'm doing well, cancer is not progressing. Can we do it at a later time. So I would anticipate in these kind of designs, the amount of people who ends up not getting the sequential intervention without progressive disease is not necessarily a bad thing. It can be a consequence of patient preference because he has that ability to push back because tumor is not getting worse. So we do see that in clinical practice. And so it's something that, on one hand, we're assigning it to chemo because we think it's aggressive disease. We want to do chemo. On the other hand, if TLX511 is effective, some of the patients very likely can push it back for a later time.

David, I'll just add to what Dr. Barata said. I think we've articulated the purpose of Part 1 of the study. FDA wanted to see specific information on the priority combinations of RP plus TLX591 when they're intended to be given together or 591 sequenced with docetaxel following. Prostate SELECT, you might recall, I don't expect you to during all of these details, you got other things that you think about no doubt that Prostate SELECT, the primary objective that as the title of that study said was to demonstrate that gallium PSMA TRACE indicated where lutetium rozopanimab therapy was likely to go. So in Prostate SELECT, we didn't specify that the patients had to have an RP or a chemotherapy agent. We allowed it that the vast majority of patients in that trial were treated as monotherapy with 591.

Your next question comes from David Lowe from UBS.

Just going back to Slide 15, we saw enzalutamide group showing platelet count continuing to decline after 150 days. Just wondering what -- how we should understand that? And do you think that platelet count is manageable after day 350?

Yes. Thanks for the question. That sort of decline, if you look at where it's happening in the platelet count, it's a long way out to the right. If you look at the sort of, I guess, the scale on the bottom, the patients heading out up to a year and beyond. So really, in this advanced metastatic castrate-resistant population where they're being treated, as I mentioned in the baseline demographics, they're being treated as second-line patients, the median age of 77, this is a pretty advanced group of patients. So that lab profile is certainly not uncommon in the broader population of patients.

Now whether it's any more marked with abiraterone or not, I don't think these data can conclude that for us, but that behavior of that decline sort of out beyond 250, 300 days is pretty characteristic of what you see to the blood counts if you took them and sent them to the lab in the average patient who was off study. Maybe Dr. Barata, you could comment in your own clinical experience, what happens to the lab counts after long exposure to abiraterone?

Yes. No, that's a fantastic point. I would argue as well. You have 25% in the baseline patients previously exposed to taxane-based treatment, right? Elderly population, median age, close to 80, 77, which is definitely higher than the overall population, if you will. We do see some cytopenias with ABT and ARPI. So I don't -- and if you look at the numbers, the numbers is definitely within the safe zone for us to definitely consider subsequent therapy. So it wouldn't got our eye in terms of concerning at this point with such a good -- I mean, a follow-up of the year, as David alluded to, it's kind of reassuring thinking that they got therapy a long time before this last cutoff. So that's, in my view, it's aligned with what we would anticipate for this patient population.

Okay. Just the other one I had, with the next steps with the FDA, what are your thoughts on what the safety criteria might be to proceed to that 2?

Really, look, I think this will be the last question, but it's an important one. The FDA were crystal clear. FDA wanted to see safety on the concurrent use of TLX591 plus very conventional agents in the U.S., which are primarily abiraterone or enzalutamide or if a clinician like Dr. Barata wanted to provide docetaxel after TLX591. They were 3 dosing regimens that the FDA was crystal clear on. It was prespecified by the agency go away and do 10, 10 and 10. We've actually done 11, 11 and 14. So we've done a little bit more than what the FDA asked for. But that was prespecified, pre-agreed with FDA, and we look forward to taking it back.

The only other thing that the FDA would want to make sure is that the agents don't preclude subsequent treatment with chemotherapy, and we've got that data as well, and we look forward to presenting that to the FDA. So we've done what the FDA agreed, all prespecified, and we're about to take it back and show it to them.

So I think that's -- yes, thank you. Great question. I think we're out of time. I'll hand back to the operator.

Thank you. Yes, that does bring us to the scheduled finish time. I'd now like to hand back to David for any closing remarks.

I'd like to acknowledge the -- obviously, the patients that have come into this trial, all 36 of them, including the 57 that were screened, but of course, dedicated clinicians that we are thrilled to work with like Dr. Barata, very esteemed investigators across North America, Europe and Australia and New Zealand. I'd like to thank those for dialing in. I hope it's been informative to you. So thank you very much.

That does conclude our conference for today. Thank you for participating. You may now disconnect.

Good morning, good evening or afternoon, depending on where in the world you are. My name is Ky Williamson. I'm SVP of Investor Relations and Corporate Communication at Telix.

Very pleased to welcome you all today to our webinar with some key opinion leaders and special subject matter experts to discuss a physician's perspective on innovations in PSMA PET CT imaging for prostate cancer.

Today's format will be a moderated panel discussion hosted by Dr. David Cade, MD, Chief Medical Officer -- Group Chief Medical Officer at Telix. I'm very pleased to welcome our speakers. We are joined by Rodney Hicks, Professor of Medicine at the University of Melbourne and Monash University, Founder and Executive Chairman and Chief Medical Officer at the Melbourne Theranostic Innovation Center. and by Dr. Paul Yonover, Chief Data Officer and Director of Clinical Navigation at UroPartners, a division of The Specialty Alliance, Chief of Urology at Ascension Saint Joseph Hospital from Chicago. Thank you for joining us. And last but not least, Darren Patti, the Telix Group Chief Operating Officer.

Today's format will be a moderated panel discussion, as I said. [Operator Instructions] If we can't answer your question during the session, we'll follow up after the call if necessary.

With that, I would like to hand over to David Cade.

Thank you, Ky, for the very gracious introduction and very excited to be here today to discuss what I think is a critically important topic, which is the future of prostate cancer imaging.

We are joined by 2 of the global leaders in the field, Professor Rod Hicks, who is an esteemed nuclear medicine physician and Dr. Paul Yonover, who is a leading surgical urologist based in Chicago.

We're going to cover 3 very important themes today, namely the current clinical landscape of how we image prostate cancer. We're going to also cover the supply chain, which is an important consideration, as we aim to serve patients across geographic expanses. And I think most excitingly, we're going to address a key question, which is what are our needs for the future. We've made some very significant advances in the last 5 years, but where will we go over the next 5- to 10-year period.

So to kick things off, I'm going to ask Professor Hicks. Professor Hicks, you installed the first PET/CT camera in this country in Australia and one of the first in the world at the Peter MacCallum Cancer Center in 2001. It's almost a quarter of a century ago. And then you commenced our specialized PSMA PET imaging and therapeutics, which is what we call today theranostics at Peter Mac around 2015. So that's over a decade ago. So could I start by asking you to provide an overview of PSMA PET imaging and some of the key data that supports Gallium PSMA PET and how Gallium PSMA PET has changed the way we manage men with prostate cancer. So what really matters to physicians today.

I think we've seen over the last decade, David, a really strong clinical support for the use of PSMA imaging in the urology community at 4 different stages of the process of diagnosis and therapeutic planning.

In the diagnostic setting, although MRI has a pivotal role in localizing prostate pathology, it's a technology that is firstly very difficult to read. The MR radiologists, who are good at prostate, they are, in my mind, the idiots of the [indiscernible] imaging world to bring together an incredibly complex set of images to make a diagnosis.

And they use a scoring system called PI-RADS, the prostate imaging radiology diagnostic score, which I sometimes tongue-in-cheek renamed the poorly informative, really accurate diagnostic score because it's really very observer dependent. Men hate prostate MRI. I can tell you that, and there are many who can't have it.

And in that setting, PSMA has a very high acceptance by the patients. It's got a very good sensitivity for the detection of disease. And it also moves on to the next phase when you've already made the diagnosis of prostate cancer on clinical grounds and biopsy. it's excellent for staging the disease. It has a high true positive rate, high diagnostic performance with diagnostic micro metastases down to very small levels.

And that becomes particularly important in the next phase, which is in the biochemical recurrence after definitive treatment, the PSA hasn't gone away. We know they have disease. We have a very sensitive and specific biomarker for the presence of residual disease and that biochemical recurrence, we can see disease down to very small levels with PSMA PET scanning.

The next level is after patients have developed metastatic disease, determining their therapeutic pathway and particularly selection for radioligand therapy theranostics, the pathway of -- if you can see it, you can treat it and high PSMA expression is [indiscernible] for selection of those patients.

And the last phase, and this is something that's just coming along and recently been incorporated into the prostate working group for assessment of response to therapies is the use of PSMA for monitoring therapeutic response. The principle, if you can't see it, you can't measure it, you can't monitor it. And at all stages, we've been able to show that PSMA outperforms CT bone scan. So why would you use a technique that can't see the disease in the first place to monitor that disease. So it's really having a fundamental role at all stages of the evolution of the prostate cancer spectrum.

Thank you, Dr. Hicks. Now if we go to the next slide, please. Dr. Hicks, this is the most recent Phase III study. So it's a Phase III study of Gallium PSMA PET. In fact, this was in a Chinese population that's a pivotal registration trial intended to see Illuccix approved in China. That's in 140 patients. And really, this is a very positive Phase III trial. The results came out recently a couple of months back. And really, the headline results was that it showed that there's a very high positive predictive value of gallium PSMA PET across high to very low PSA strata. And it also showed very high positive predictive value across different anatomical locations of disease in Chinese men. So did these results surprise you? Or are they otherwise what you would expect?

Yes. They don't surprise me at all. I think we've got now a very large body of data from around the world with a whole variety of different quality of imaging technology that have shown very high positive predictive values and pathologically validated studies as well, demonstrating a high positive predictive value.

The area, I guess, that we're seeing the greatest impact, however, is actually below in those very low PSA levels, where traditionally people haven't been doing it. The whole point of doing PSA after biochemical failure is to identify a subgroup of patients, who are potentially salvageable by local regional therapies. And so we've seen our population, referral mix move increasingly to below PSAs of 0.2.

And in that population, we see, firstly, with the protocols and the technology that we use a very high detection rate of disease, but more importantly, a much lower rate of disease outside the prostate bed that could never have been controlled by local regional therapies, which often applied now empirically in that low PSA level.

Thanks, Dr. Hicks. If we go to the next slide, really leads me on to a technology question. Dr. Hicks, you were -- you've installed, I think, one of the first Siemens Quadra whole body PET/CT cameras in Australia at the Melbourne Theranostics Innovation Center, which you established a number of years ago. I think a fundamental question, this is a truly fundamental question is where will the next major innovation come from in the way we image men with prostate cancer? Do you think it's better tracer drugs? Or do you think it's the evolution of the capital equipment, the cameras? What's your perspective on this?

I think it's a bit of both, David. The performance of PSMA has been excellent with what I would consider last century technology in many ways that people were using analog, sometimes time-of-flight, sometimes non-time-of-flight cameras, which have rather low sensitivity for the detection of disease.

The advantage of the Quadra having a field of view of over a meter and very high time-of-flight resolution and very sensitive digital detectors is that it's about tenfold higher than the best digital camera that Siemens themselves make, which itself is about twice as sensitive as most non-digital time-of-flight cameras, which are themselves twice as sensitive as analog cameras without time-of-flight. And so you're getting somewhere between 10 and 40-fold higher sensitivity. And that makes a big difference in terms of the signal to noise, which is particularly important to detecting small volume disease.

So this is a patient who was planned for salvage pelvic radiotherapy on the basis of an elevated PSA of around 0.4 thought to have perhaps a false positive in the rib. We do see some false positive uptake in rib lesions and with any of the PSMA agents more with some than others. But this patient was still going to have an attempt at cure or at least delay of need for systemic therapy by pelvic radiotherapy. And they came to us for some therapeutic radiotherapy planning and had PET imaging on the Quadra.

The image on the left in red, it was the conventional scan done outside our facility, a 32-minute scan on a standard field of view digital camera. And the images on the right are the same acquisition, but then passed into shorter and shorter aliquots of the acquisition time. Our standard acquisition is 4 minutes for that partial body, but we've processed it down to just 30 seconds of that acquisition.

And you can see that what was perceived to be local retinal disease clearly isn't. There's widespread disease. This patient never would have benefited from pelvic radiotherapy. But more importantly, around the pelvis, we can see with late diuretic imaging, post-diuretic imaging, there's almost no or very low activity in the bladder, but there's no evidence of recurrence in the prostate bed.

All of the toxicity from radiotherapy comes from irradiating the prostate bed. And in this patient, not only was it not necessary, but because there was disease outside the pelvis, there was no potential long-term progression-free or overall survival benefit in this particular patient. So huge impact on patients.

So that idea of the reasons we don't see disease, 3 reasons: too small, too close, too close to the bladder, too close to the major blood vessels, waiting longer, imaging later allows clearance of blood pool, and you can see very small nodes close to the blood vessels or too little expression of the target.

Technology helps with too small, the Quadra and other extended field of view digital PET scanners are going to make a big difference and AI processing of those data are going to make a further jump in the improvement in the sensitivity.

To close, it's about technique, imaging before the urine gets in the bladder dynamically, which we routinely do in our biochemical recurrence or imaging late post diuretic. And again, more sensitive scanners allow you to go longer into the decay scheme and still have high statistical quality scans.

The last question is too little target, you need different tracers, new PSMA tracers aren't going to make a big difference if the target isn't expressed anyway.

Maybe just while we're on that topic, you could touch upon the loss of the PSMA target from a prostate cancer and what other tracers might be required to hit other alternative targets that are manifest on a prostate cancer cell.

There's sort of 2 different scenarios wherein PSMA is not expressed. The most important one is where the disease becomes highly differentiated and disorganized and loses the basement membrane, where PSMA is expressed. And that's Pattern 4 -- sorry, Pattern 5 Gleason score.

And so that gets into the very high isotope grade group, so particularly grade group 5, where either 4 plus 5 or 5 plus 4 or 5 plus 5, depending on the proportion of that classification of 5, which often lacks PSMA you'll get very low uptake. 4 has high generally PSMA expression. 5 has -- can have none.

And if there's a high proportion of Patent 5 disease, those cases can be relatively negative on -- in terms of expression on staining. And so those patients, they're genuine card-carrying cancers that use glucose and FDG PET has been shown to be very, very useful and an adverse prognostic indicator. I actually believe they're the subgroup of patients, who benefit most from chemotherapy.

So if you've got one of those very high Gleason score in a negative PSMA, I think it's really important to do an FDG scan in those.

At the other end of the spectrum, as you get into clinically significant prostate cancer that transition from 4 -- sorry, from Gleason 6 to 7, for example, some of them have relatively low PSMA expression, particularly if the percentage of Pattern 4 is relatively low. And that may have prognostic significance, but there are other targets that are overexpressed in that group and particularly GRPR sensitive, which is the gastrin-releasing peptide receptor.

And I think there's some exciting work going on in that area of new tracers that may have both diagnostic and therapeutic applicability in terms of target. But there are other targets that people are obviously looking at both stromal as well as epithelial that may be important.

Yes. Thanks, Dr. Hicks. I mean it's evident that you're operating at the bleeding edge of technology and camera equipment and that's really manifest itself in the success of your theranostics practice in Melbourne.

I'd like to now transition to the surgical perspective. Dr. Yonover, you're a very busy surgical urologist at the largest private urology practice group in the world based there in Chicago. So we've gone from Melbourne to Chicago just now. You're also effectively a business owner in which your practice currently has 4 PET/CT scanners. And I believe you're investing very heavily with your partners in more cameras. Your practice group currently sees and images over 1,000 patients a year in providing a PET/CT scan and you treat those patients under your own care. So how has PSMA PET imaging changed your practice? And what's important to you in your U.S. high-volume practice setting?

Sure. And thank you very much for having me. It's a pleasure and certainly an honor to be with somebody like Professor Hicks. So thank you, Dr. Cade.

Yes. So I represent, I think, a growing sort of segment of the U.S. health care system. I'm in a private practice, essentially single specialty group. We're now fairly massive. We're national. So those scanners that we're putting up are in towns like Detroit, Michigan, Philadelphia, Chicago, New York, et cetera. I think by 2026, we should have 13 or 14 scanners up. And that's with the idea that a large group like us in the United States is sort of a closed ecosystem, at least that's what we aim to be.

And that -- and PSMA PET molecular imaging really plays a sort of an integral role of that because we're part of the gatekeeping. We're the ones who screen for prostate cancer. We diagnose the patients. We have our own pathology lab. We have our own in-office dispensary because we deliver those therapeutics. We also have our own linear accelerators. So we deliver the radiotherapy, brachytherapy, we do theranostics. So we really try -- we've attempted to have a relatively closed ecosystem, where we're really going from cradle to grave, if you would.

And molecular imaging has had a massive -- I mean, it's hard to overstate from a clinical perspective from prostate cancer as a clinician, the impact it's had just in the last 4 or 5 years when it's really come to fore here in the United States and how it's been disruptive in a good way, right?

Right now, we're seeing it in the -- of course, in the diagnostics space, in the therapeutic space and of course, in the advanced prostate cancer space, what we're looking towards, what we are hoping for is expanded indication, getting a lot more clinical data and an expanded indication so we can bring molecular imaging, Gallium PSMA PET into the pre-diagnostic space in the screening space, in the active surveillance space and the focal therapy space.

And of course, as Dr. Professor Hicks alluded to, response to therapy, right? When a patient goes for radiation therapy, all we have really is following serial PSAs, conventional imaging doesn't do much and having some assessment of response will be sort of key.

But your question was how is it impacting us as a business owner, right? Because it's impacting me as a clinician, how do I approach my patients, the confidence I have in being able to truly understand do they have localized disease? Do they have locally advanced or metastatic -- cold metastatic disease? What's the volume of their disease, PSA as a biomarker, we could have hours of conversation just about that.

But the impact on a -- such a large group as ours, the operational economic impact, right, profound, right? It's actually becoming integral to our business planning. And because having access to our own scanning lets us control things, which is a good thing most of the time. quality control, we can stay ahead of things as far as technology, and we can, of course, leverage this from an economic perspective.

But as a large group here in the United States, large private groups outside of academia is actually probably one of the largest sources of clinical research, clinical trials. We have a lot of very busy, very sophisticated clinical trialists.

And so it's sort of that 3-legged stool, right? There's a clinical piece to this that is immediately, tangibly impactful both to the physician and to the patients that we treat. It is certainly impactful to a large for-profit company like ours, where we're looking to the economic benefits of having this in our ecosystem. And then there's the clinical research piece. So I would say that's having access to PSMA PET scanning really has been quite disruptive to all 3 of those pillars.

Yes. Thanks, Dr. Yonover. What I'd like to do is maybe delve a little bit deeper on 2 elements of what you raised, namely the business model, but also the clinical research that you contribute. So we'll just address those. Maybe you could talk a little bit about the requirements of a high throughput 6-day a week business model where you're clearly investing very heavily in camera capital equipment. What are the requirements of that and the requirement to have reliable clinical efficiency?

And then we might talk about some of the patients that you might even have seen today on BiPASS, which is a rapidly enrolling trial that you and Dr. Hicks are both co-investigators on?

Right. So I mean, I can't again overstate the importance of efficiency. This is the word as a business owner, right? Anything that kills efficiency is something that's sort of an enemy to our mission. And so we've had to spend a great deal of capital, both tangible capital as well as just labor on operationalizing a high throughput system, right?

We have a massive footprint. So just our subpractice here in Chicago has a massive geographic footprint. And so we've got patients. It's a spoken wheel sort of referral. We have one scanner. We're hoping soon to have another just locally. And -- the coordination of care, quite considerable.

These patients are of various ages and capability as far as transportation and mobility and getting patients scheduled, getting the prior authorizations and the other issues with insurance that we deal with here in the United States, getting a patient there, getting them scanned, getting them home, getting the scan, getting the data.

I mean it's a -- when we're doing just on our 1 camera, 1,000 to 1,200 scans in a year, then of course, there's force multipliers, right? As you get bigger, those small changes in efficiencies you bring up, anything that can hinder efficiency is something that's something we try to eliminate, right?

So we have to get a lot of patients through. It's logistically quite challenging. It's -- we have here in Chicago O'Hare Airport. And it's nothing short of that, right? So no-show rates are a big problem that we want to eliminate, right? And it's same-day scanning. That's really the only way we can really truly achieve sort of our high throughput.

And from our perspective, right, we are always looking for optimization, right? Any business, whether non-profit or profit driven should always be looking for optimization. We've made a choice to go with gallium-based isotopes in our scanning protocols. And as Professor Hicks so eloquently sort of pointed out and just demonstrated, right, the optimization opportunities are in our technologies, our techniques, our acquisition protocols, the application of AI-assisted interpretations.

That's what as a group, we're going to be looking to as we scale and as we try to get that 6-day a week. I hate the visualization, but we got to pack them in, right? That's a group like us, that's what we have to do here in the United States. That's -- those are the -- we're under the same economic pressures as anybody else. And so, we have to live within the physics of gravity and the physics of economic pressures.

And so we obviously don't want to cut any corners clinically quality-wise, we want the very best. We want the very cutting edge for our patients. But we need to do that in the most cost-efficient way in a way that's not going to be disruptive to our overall very complex ecosystem that we've built. So we're looking towards those improvements in technology that Professor Hicks went through so that we can get better scans.

And in the same vein of trying to provide cutting-edge, high-quality care, we are participating in the BiPASS study, which I have great cautious optimism that based on already published data, but also just from my clinical experience, that if you're able to bring in a PSMA PET into the pre-diagnostic screening space, Professor Hicks, of course, made me laugh about his descriptions of the PI-RADS reading system as a clinical urologist whose job it is, is to find prostate cancer and only find clinically significant prostate cancer and only treat appropriately. The advent of MRI 3, multiparametric 3 Tesla MRI was a huge advance, right?

We all understood and we were sanguine about its shortcomings, but it was -- really came to the fore in essence of a vacuum. And it was game-changing, a little bit of a trite saying, it was game-changing, but we were fully aware of MRI negative -- MRI-invisible disease and sort of the ambiguities of a PI-RADS 3 lesion.

And so we've already gotten the sense that a PSMA plus an MRI, they're very complementary. They're actually not exclusionary. They're complementary in many respects. There are 2 different modalities and prostate cancer is a heterogeneous disease, PSMA expression. We're just at the surface of understanding the biology of PSMA expression.

And so if on an MRI, we can image and understand the ADC and the other areas, where the prostate -- how it looks under MRI imaging. And then we're able to use a molecular target like PSMA PET. You put those 2 together, you look for congruence -- incongruent areas. It should in theory, and I think it will bear out, be able to allow someone like myself to have a more effective biopsy, a higher yield and/or -- and sort of the other aspiration is biopsy avoidance, right?

If you have great clinical data, particularly given the pretest probabilities, some of the clinical parameters, if you have a negative MRI and a negative PSMA PET scan, the hope of the BiPASS trial and other data is that perhaps we can avoid biopsies in certain patients. It will also be interesting to apply that in the active surveillance space.

And my hope is on that end, right, to be able to avoid biopsy in certain patients of mine, but also be able to do a better biopsy for patients of mine, where I'm able to have a higher yield that's more efficient. And then if I have a biopsy that tells me a little closer to truth what's going on in that prostate, that's where I can help guide a patient make better therapeutic decisions. Is a prostatectomy or radiotherapy or metastatic-directed therapy, systemic therapy, clinical trials. When you're getting closer to truth, right, you can actually just make better decisions.

And so that's -- I did 2 BiPASS biopsies today. These were 2 gentlemen's actually who had negative MRIs, and they had minimally avid areas of disease, one that I'm suspicious, I covered it pretty well on the biopsy. And it's an area actually that I would not have ordinarily gone and biopsied on a normal template transperineal biopsy on a negative MRI.

So obviously, I'll be very curious on my own experience. I'm also obviously going to be very curious about the readout of BiPASS when it's available. But I think there's really no doubt that the data that comes out from the BiPASS trial is going to be highly useful. There's just really no doubt about that, particularly based on some of the stuff that's come out of Australia already in that space.

So I'm -- and as a business owner, right, I'm looking for -- I've got a scanner, I've got a tracer that works beautifully. I'd love to find more applications in the screening space, in the advanced therapeutic space and in that response to therapy space.

Yes. Dr. Yonover, thank you very much. Look, that's a very comprehensive overview. I think to summarize, as a surgeon, your raise on [ detra] , if you will, is to do a complete cancer surgery on a patient and make sure that you have cleared the patient of all prostate cancer.

You've also made the point that you've got a lot of patients to serve. You've got an extraordinary high throughput clinic with your partners and you've got a significant requirement for PET camera uptime to make sure that you aren't seeing those assets not run to their full extent.

So that really moves us on to the second theme, which is supply chain and making sure that the ability to use those cameras to image patients to be able to take them to surgery is maximized. So we'll move across to my colleague, Darren Patti. Darren, prior to becoming the Chief Operating Officer at Telix, you were instrumental in the leadership team at Sofie as well as before that [indiscernible] PET trace and manufacturing business as well as their radiopharmacy networks in North America.

Today, we've got 2 isotopes, obviously, Gallium-68 and Fluorine-18, effectively serving the PSMA PET market. Perhaps, Darren, you could start by talking about the supply chain for gallium and how that's supporting the broader patient access as well as production flexibility, which is what Dr. Yonover just talked about.

Yes. Thank you, David. Yes. When you look at the gallium landscape, you find that there's really a -- what we have now is a mature and robust supply chain. Now that we have multiple commercial products on the market for a number of years now, this has really given opportunity for the gallium isotope supply chain to mature.

And because of this, I think there's a few notable things to call out. And this includes that now we have multiple generator manufacturers that have demonstrated consistent, reliable access and delivery. And this is something we expect to continue to expand with additional product offerings in the future.

Additionally, the beginning to end supply chain of generator production has become more vertically integrated with various manufacturers. So that further ensures uninterrupted supply. So that includes starting material germanium that's needed for the generator manufacturing

And then we talked about the flexibility and access and then just the inherent nature of having a generator on site or nearby essentially provides on-demand access, and that really affords the kind of ultimate flexibility for patient demand and access.

And then finally, with newer generators having higher capacity, this availability in the market further drives that flexibility and additionally provides greater access. So we've established that we have a very solid and consistent gallium generator supply chain that's available for patients.

So -- but now we can take a look and augment that or scale that even further now that we have commercially available cyclotron produced gallium methods. So that really allows us to ratchet up isotope production even further.

And this includes things like the ARTMS technology via the QIS system, and this allows large curie amounts of gallium to be produced. And again, this is using a very secure end-to-end supply chain, so we know it's reliable.

And so when you sum up the parts on the isotope side and then couple it with a higher capacity kit as an example, like Gozellix, you really have that higher flexibility solution that can easily scale to meet patient demand.

So on the next slide, it's just really an illustrative example of when you look at the over 250 partners that are producing Illuccix and Gozellix on a daily basis and then you add on capacity afforded by Gozellix in conjunction with high-capacity generators or cyclotron produced gallium, and you can see how it really opens up access with the associated flexibility to a very broad customer base

So I think the take-home message here is that with Illuccix and Gozellix, paired with an extremely reliable gallium generator supply chain, including generators of various sizes, and the option for a high-scale production via gallium production on a cyclotron using something like the ARTMS technology, there's a flexible option that can be tailored to a specific market need. And I think that's a very unique offering.

Yes. Thanks, Darren. I think obviously, let's put it this way, gallium and fluorine have been workforce isotopes over the last 5 years during the advent of PSMA PET. There are also exotic isotopes, if you will, copper, zirconium and others. So now we possibly have 2 providers aiming to bring copper-based tracers to the PSMA PET market.

In your view, I mean, you've got over a decade of experience in meeting demand and doing so with very high reliability. Are these providers with copper going to be able to replicate or meet the reach of the existing gallium and fluorine supply chains? What's your view on that?

Yes. So it's a really good question, David. And obviously, supply chain success is a prerequisite to deliver commercial success and patient access, right? So -- and we saw some of those challenges early on in the gallium market. And as time has progressed, the market has grown to meet that demand.

And I think we're a little bit early in that phase with copper. There's just some product attributes that make it a little bit different to look at as well. You have a longer half-life. So conceptually, you can have more centralized manufacturing, but that doesn't come without fair logistical risks and limitations as well. So in my view, it's still better supported with maybe a more regional model.

But to your point, that's -- there's up-and-coming products, but I don't feel the -- really the supply chain is quite there yet, and that's from starting materials all the way through finished product.

So with the gallium, it's truly something we've seen that's battle tested and really pressure tested through -- in a high capacity and high demand mass market. So I think it will take some time to get there. There's emerging technologies and things that are being done, but that's going to take some time to develop further.

Thanks, Darren. Well, let's assume they do get there. I might direct a question back to Professor Hicks. Professor Hicks, in your mind, in your experience, given the background of what you described was possible with improved camera equipment. Is there a role for new or novel isotopes? And if so, what might they be? Are they niche roles? Or can you see a broader application?

Yes. I can talk, I think, to some extent around the copper development because the agent that's currently in clinical trials, the bisPSMA was actually developed through my lab in collaboration with Professor Paul Donnelly from the University of Melbourne, and we did a lot of the preclinical and some of the earliest imaging of that agent.

And the advantage in the preclinical model was we saw as a companion for the therapeutic application of copper 67 that the long half-life of copper 64 of 12.7 hours allowed you to get a time activity curve that could do predictive dosimetry for the first time, a long enough uptake and clearance curve to estimate the dose that would be delivered to tumor into normal tissues.

And we saw a major advantage in that, particularly in the patients who are a bit borderline for selection of PSMA-targeted therapy where the intensity of uptake is not particularly high, and you worry about the therapeutic index between radiation delivered to tumor versus to normal tissues like salivary glands, like the kidneys.

So we certainly thought there was going to be a significant advantage there that the ability to image late would allow that issue of being too close to blood vessels or bladder would be addressed to some extent by late imaging.

And from that point of view, the long half-life being able to image at 24 and we've imaged here out to beyond 48 hours, which on the Quadra because it's so sensitive with copper, you can go very, very late in your imaging protocol.

But it's -- if you look at the sensitivity of the gallium PSMA and the convenience that in most patients within 1 to 2 hours, you've got all the information you need for therapeutic pathway planning. I was struck by what Paul was saying about how it's impacting management.

Before PSMA and even with multiparametric MRI, surgical planning and medical therapy planning, radiotherapy planning was treatment by Braille. You were treating completely blind. And by -- the real impact is not just simply the positivity negativity, it's where the disease is that's critically important.

We found that between 30% and 40% of even pelvic confined nodal disease is outside traditional empiric radiotherapy treatment volumes. They're not areas that surgeons like to go, but they can go if they know that the disease is there. And so it's making a huge impact on that planning piece.

And so I think that these agents are going to have a role. And increasingly, people are also using tracers for radio-guided surgery, where you use a probe on a robot often increasingly as well as optical imaging, and this is work that we're doing with Telix, as you know, David, to combine radioisotope and optical probes for imaging-guided surgery, the macroscopic planning with the PET scan, the microscopic at the level of the operating microscope and robot.

Yes. Thanks, Professor Hicks. I might just move to the final sort of theme, which was do we need a new tracer. And I might direct this question to Dr. Yonover. Given the discussion up to now on the current clinical landscape and the supply chain aspects that Darren covered of the U.S. PSMA PET market. In your practice setting, a very large or the largest private urology group in the world, let me pose a question to you. Do you need a new tracer? And if so, what for? And what might be the necessary conditions in which to implement it? Does it have to be same day? Or can you accommodate second day, third day, fifth-day imaging? How would it work in your practice?

Well, in a short answer, no right now. In 2026, particularly because we've already created a business plan around gallium scanning, right? The bar would have to be set extremely high for us to not only change and adopt a new isotope, but if that comes with a whole different logistical landscape, right?

That -- those logistical challenges, while not insurmountable, certainly are a barrier that would give us pause. And for those -- from that pure business model perspective, I know that it would be very challenging and it would create sort of -- it would create a big problem for us.

And so I go back to -- we hope to optimize things with technology. I'm -- as a clinician and a business owner, I'm much more interested in novel targets because I know I've seen it myself with my own patients, the shortcomings of PSMA targeted imaging, both in the theranostic space, of course, but in the newly diagnosed space. So I think that's what we're going to be looking for in sort of a short answer.

The other thing from the clinicians and certainly, Professor Hicks could speak much better to this than I, but these tracers are not interchangeable. This is not -- we have -- as a clinician, as a non-nuclear medicine doc, as a urologist, we've had to ingest all of the molecular imaging and most of that is gallium-68-based literature over the last 5 to 10 years, of which there's a great depth and breadth.

And any new tracer is going to have to not only show clinical utility, it's going to have to show not only change in management, but it's going to have to show the impact on outcome, right? And that takes quite a long time.

And until we see that proof, right, it would be hard for us to justify from a logistical challenge, a business challenge to make those sorts of leaps. I see -- and again, just from the clinician's eye, not as from an expert in isotopes, but I see something like copper as a niche product, right?

There are instances, where our gallium 68, which I see sort of as our daily workhorse. There are going to be times, where I think it's probably going to be useful in that space. But I'm personally much more interested in different targets than I am in different isotopes.

Thank you, Dr. Yonover. Look, I think that's a very comprehensive answer. And I think we will conclude the formal session there and move to questions-and-answers. So I would like to, on behalf of the audience, thank Professor Hicks and Dr. Yonover and my colleague, Darren Patti, who are really sort of apex predators right at the top of their fields, as I think you can determine from some of the discussion.

I will now -- perfect timing, it's 10:20 here in Sydney. I'd like to leave 10 minutes at the end for questions-and-answers, and I'll do my best to direct the question to the appropriate respondee.

What I'm going to do is I'm just going to go through the questions as they come in. The first one is there's a lot of noise around BCR sensitivity. I think what that means is that people are asking questions about the sensitivity of different tracers in the biochemical recurrent setting.

On the weekend, we saw POSLUMA head-to-head versus PYLARIFY. In a few weeks' time, we'll see full data from copper versus gallium. That's obviously at the EAU conference. What are those strengths and weaknesses of head-to-head study designs in the BCR setting? I might direct that to Professor Hicks, if you --

Yes. I think it's a really important question of what are the selection criteria of the patients entering into those head-to-head. I think the data actually has been already presented around the gallium PSMA 11, the Illuccix versus the copper agent of Clarity that my colleague here in Australia, Professor Louise Emmett presented at [ EUA ] (sic) [ EAU ].

If you look at the data, and this was in a group of patients, where I think the median PSA was about 0.4 with an interquartile range between 0.3 and 0.6. If we go back to that data that you present from the Chinese study, the positivity rate in that series for that range was over 90% in Louise series, it was 28% for Illuccix, which is just completely out of keeping with that data, but also out of keeping with her own data in 3, I think, published studies, where she's published her results with Illuccix, where in that sort of range, she was getting well over 50%, closer to 75% of a positivity.

And to me, that speaks to the potential of this group being subject to a selection bias that because they have the Illuccix first, and I suspect they either had negative or equivocal scans or their PSA was out of keeping with the level of disease detected on their scan and remembering that, that scan was done probably around 45 to 60 minutes, not at 60 minutes, not beyond 120 minutes, not with diuretic, not with dynamic imaging.

And so they're the very group of patients, where the technique and the technology is going to make the biggest difference in detecting them. And of course, if you then have late imaging in those patients, you're going to see more disease.

But how much does it benefit you to go to 24 hours when we know that the uptake kinetics really plateau off at about 3 hours. And if you can image at 3 hours going to 24 hours or you lose the statistical quality in your image.

The other limitation of that approach is that because of the long half-life, we're restricted in how much we can inject into a patient. The administered activity for copper within the radiation guidelines are much less than for gallium and also for fluorine, which have a much shorter half-life.

So you're starting from a lower statistical background and imaging later. And so there are significant offsets as well as the supply chain issues that Darren brought up that I think are going to really mean what Dr. Yonover was talking about. There is going to be a place for this and it's in exactly the kind of patients that I think Louise is may be inadvertently preselected those who have a negative scan on a conventional PSMA agent or the extent of disease just doesn't seem in keeping with the PSA level that's extent in that patient.

Yes. Thanks, Rod. That's a very comprehensive answer. We are being very egalitarian here because this is obviously a surgical question for Dr. Yonover, which is nice to see. Thank you to the questioner. The question, would PET-guided biopsy reduce the number of cores required and the number of cores required to calculate the Gleason score and does higher yield mean the ability to acquire more cancer cells per core due to PSMA PET guidance. How would you tease that out, Dr. Yonover?

That's an excellent question. I'm still -- that's sort of to be -- I don't mean to be cute, but I think that's to be determined, right?

One of the things in our MRI fusion experience, meaning we -- our MRI experience of whether we do a template biopsy, basically a systematic biopsy, where we're taking cores from various regions and then also targeting the region of interest. That is, I wouldn't say controversial, but that's batted back and forth. And I think we're going to be facing the same sort of conversation with PSMA.

I don't know if the number of cores will be reduced. It's not really impactful as far as morbidity. The number of cores taken don't particularly increase risk of infection bleeding or patient discomfort, to be honest. It's more of biopsy, no biopsy. Once you're starting to biopsy, that impact is de minimis.

What I'm more interested in from a yield perspective is the reduction of occult disease, right? We do an MRI fusion biopsy. We think the patient has a Grade Group 3 disease. Thankfully, we have molecular imaging now so that I can avoid therapeutic futility. We know if the nodes are likely to be positive. We certainly have ruled out metastatic patients so that we take the patient to surgery. We're confident that at least they don't have metastatic disease.

And lo and behold, what we want to reduce are the surprises in surgery, right? We want to know going into surgery, what is the most likely grade group and where it is? Is there SV involvement? Is there extra capsular invasion so that we can do a wide dissection on that side. Those are the things that we're hoping that PSMA plus MRI, we're going into surgery with more certainty. That's where I'm hoping for higher yield.

The other area, right, is if there is -- and this gets into a little wonky into the biology of prostate cancer, but if you have, say, Grade Group 5 non-PSMA excreting disease, right, that has some neuroendocrine features, that may not be responsive to the radiosensitivity of that disease, it may not respond, right?

The advantage of surgery is that it's agnostic to the biology. If it's localized and you take out the prostate, it's gone. If you go for radiotherapy, you have to apply various levels of boosting, radiotherapy, systemic therapy and the response to radiation is variable because we know the heterogeneity of prostate cancer is variable.

And then if I may, just for a moment, from a surgical perspective is focal therapy has been underutilized, and that's partly because surgeons like myself are very reluctant. We know it's a heterogeneous disease, where we always want to avoid missing disease.

And if I have a higher yield, more accurate biopsy, particularly if there's congruence between my molecular image and my MRI, I think the field of focal therapy will start to bloom, which is going to be an advantage, particularly for our younger patients if we can go into focal therapy with more confidence.

And that confidence is borne out from a better biopsy. That's a long-winded answer to your short question, but hopefully, that's the promise of where we can get from the intraprostatic findings of Illuccix.

Thank you, Dr. Yonover. I think Professor Hicks you --

I just wanted to add a very quick thing to that. There are areas, where I think both MRI and biopsy are very difficult. One is the anterior fibromuscular stroma, which can be hard to get to with the biopsy needle. And it's also a more difficult area to interpret on MRI.

And we've seen a very significant impact of PSMA in that particular area, identifying the other areas right up at the very base, close to the bladder where the needles -- they're a little bit reluctant to go so high. And we've certainly seen cases where biopsy negative, but strongly positive on PSMA because they -- it's just a sampling error. And so I think that there is a big advantage there.

We've -- I think, today doing our 51st patient on the BIPASS study. And the fact that this has been run by the Australian Prostate Cancer Center Urologist shows that their enthusiasm for this technology as part of their diagnostic workup because not only do you get a better assessment of the extent of disease within the prostate, at the same time, you're getting staging information, not only about the pelvis, but about the whole body. And in the higher PSA, higher-risk patients, there's a significant yield of staging information, not just diagnostic information.

And that's efficient for a large practice like us, right? That efficiency, the "one-stop" shopping, right? The number of visits a patient -- if we can cut down on the number of patient visits if we can -- part of our business model is navigation, right, navigating these patients. And that's one of the reasons why we've adopted molecular imaging internally and just helps us navigate these patients.

And what Professor Hicks is talking about, I'm glad to see that the enthusiasm I have no doubt would be in Australia would be as great as it is here in the United States about getting PSMA PET in the pre-biopsy space. I think there's just --

I don't want to scare you, but last year, we did over 5,000 PET scans with a single PET scanner and approximately half of those were PSMA scans. So it's going nuts.

All right. Thank you very much, Professor Hicks and Dr. Yonover. We've got time for one more question. We will take any residual questions and answer them separately. This is for Darren. Darren, could you please address the breakdown between cyclotron produced versus generator-produced gallium PSMA. And could you possibly talk about the scale-up of gallium production, as we anticipate the scanning volume to potentially double by the early 2030s, which is sort of 5-odd years from now?

Yes. I think that's the scale-up is where the cyclotron production really comes into play, right? So right now, the majority of the gallium production, the vast majority is done via generator-produced gallium.

And I think there's always going to be a place for generator produced gallium, right? So there's really not a one size fits all. But the cyclotron technology gives us, as I mentioned earlier, that opportunity to really ratchet up the amount of activity we can make.

So you're talking going from 50, 100 millicurie generators to curie amounts of gallium on a solid target system via cyclotron production. So you're talking 10x to 20x the amount of isotope. So that really opens up a lot of flexibility in terms of how radiopharmacies and those producing finished drug product can address the market.

There could be a fractionation of the isotope feathering out to other centers, just opens up a new world of opportunity. And something like that is cyclotron produced gallium is something that really does move the needle to meet that surge in demand.

All right. Thanks, Darren. Well, we are just over time. I would like to, on behalf of the audience and all participants, thank Professor Hicks from Melbourne, Dr. Yonover from Chicago; and my colleague, Darren Patti, who's also in Chicago. Colleagues, thank you very much for your extraordinary insights. I've learned a lot today, and I believe the audience will have as well. So thank you kindly, and I appreciate the audience dialing. I hope it's been valuable for you. Thank you.

Good day, and thank you for standing by. Welcome to the Telix Full Year 2025 Results and Investor Webcast. [Operator Instructions] Please be advised that today's conference is being recorded.

I would now like to hand the conference over to your speaker today, Kyahn Williamson, SVP of Investor Relations and Corporate Communications. Please go ahead.

Thank you, and thank you to everybody for joining us on this call this morning, this evening, wherever you are in the world. We launched our annual report and full year results on the ASX about 30 minutes ago. We also have the slides on the screen via webcast for you to see today. I'm just going to take you through a brief introduction and some disclaimer statements before handing over.

If you just move to the Slide 2. Very pleased to have on the call with us today, Chris Behrenbruch, our CEO and Managing Director; Darren Smith, our CFO; and Kevin Richardson, our CEO of the Precision Medicine business. I should also mention that we have Dr. David Cade, our Chief Medical Officer, on the line for the Q&A session. We'll be running through today our strategy, financial results, and update on our Precision Medicine and Therapeutics business.

If you can move to the next slide, please. I am required just to give you an excerpt from our forward-looking statement disclaimer statement. So please note that on today's presentation includes forward-looking statements, including within the meaning of the U.S. Private Securities Litigation Reform Act of 1995 that relate to, among other things, anticipated future events, financial performance, plans, strategies, and business developments. These forward-looking statements are based on current information, assumptions and expectations of future events that are subject to change and involve risks and uncertainties that may cause actual results to differ materially from those contained in the forward-looking statements. These and other risks are described in our filings with the ASX and SEC, including on our half year annual report. You are cautioned not to rely on forward-looking statements, which are made only as today's date, and the company disclaims any obligation to update such statements. Please refer to the disclaimer slide in the presentation for further information.

With that, I'm very pleased to hand over to Chris to kick off the call.

Thanks very much, Kyahn, and I hope that my audio is nice and clear, and I certainly appreciate the introduction. Before Darren Smith, our Chief Financial Officer, goes into the numbers, I thought a bit of strategic framing would be useful for investors to understand where the company is heading and, of course, our key accomplishments in 2025.

Next slide, please, Slide 5. Over the last 12 months, we started to put the depth and execution around what has been a multiyear corporate development strategy. It's useful to think of Telix as a platform with these 5 major segments, as illustrated on this slide.

Moving from left to right, first up of key focus is our therapeutics pipeline, which has grown significantly and now features 3 programs in pivotal studies, as well as several high potential earlier-stage programs in rare diseases. I'm going to come back a little bit towards the end of the presentation on this topic.

Because of the explosive growth of activity in the radiopharma landscape, we have also pivoted to some extent to an internal innovation model alongside our business development activities. Clearly, when big pharma is willing to pay $1 billion for an asset that has been in a few mice, there's clearly an incentive to do in-house innovation. And so we now have a significant set of technical and clinical capabilities around fundamental R&D and discovery technologies.

In the middle of this vision and the engine room of the commercial business today is what we call the Precision Medicine business. This is far more than just an ATM machine that throws off a couple of hundred million of cash each year. It's a strategic validation of the targets we develop our therapeutic drugs for. It is more robust and streamlined clinical trials because we can see where our drug goes, and it's an early opportunity to build deep relationships with the physician stakeholders that underpin the future of the business.

Fourth, one can obviously look at sales and a commercial team simply as SG&A. We view it as building a specialty sales organization that very few companies have. Selling nuclear medicine is not selling a vial or a blister pack. It involves selling complex clinical workflows. And as our product portfolio expands, this is a strategic differentiator because it enables us to build depth with key referral physicians and drive preference towards our product.

It's also fair to note that in the major markets, this is a significant financial investment that most of our competition, both present and emerging, cannot afford to undertake. Lastly, you can develop all the great ideas you want and convince people to buy them, but if you can't deliver them reliably every single day, you aren't going to succeed.

In most industries, vertical integration is probably wasteful and doesn't offer much of a moat. In radiopharmaceuticals, where you are dealing with products that have shelf life of hours to days at most, there's a huge amount of market share ownership dynamic, intellectual property, and customer differentiation in how you deliver. This is why we have invested over $0.5 billion in the last years to better control our destiny and pave the way for high-value therapeutic products.

Next slide, please. To do all these things, you need cash, and we have a very high-growth business that made a step change this year, both through organic growth of our Precision Medicine business and through acquisition. We expect all of our revenue streams to continue to diversify and grow in 2026 and beyond, and Darren will cover this off on guidance later in this presentation.

Kevin is also going to frame this in terms of the core growth of the Precision Medicine portfolio, which is extremely exciting. The key point is we have a hyper-growth business, and it generates the cash we need to aggressively expand, further diversify our revenue and dominate the field.

Slide 7, please. This slide puts the whole strategy into perspective. As I've already said, to deliver on our bold vision for being the dominant player in radiopharma, we need a cash-generative business. We have one, and we grew it significantly this year with revenues exceeding USD 800 million or over AUD 1.2 billion for anyone that prefers their green back surge with shrimp on the barbie.

Our margins have remained extremely stable despite competition, and this excellent commercial performance enabled us to invest $0.5 billion into growing our product pipeline, funding the best commercial team in the industry, and building our infrastructure and supply chain. Think about that. $0.5 billion to grow the future value of the company from earnings without shareholder dilution. Telix is a very unique and valuable story.

Moving on to Slide 8, please. Before handing over to Darren, I thought it would be useful to give you a condensed view of our priorities for 2026. I get a lot of feedback that Telix is complicated, but it really isn't. This year is about doing three things and hopefully doing them better than we did last year.

One, we are going to continue to grow our core business around our approved products. We actually did get a new and innovative product approved by the FDA last year in Gozellix that also leverages the ARTMS isotope production acquisition. The launch of Gozellix has been successful and is not only growing our ASP and market share, it will pave the way for many future products through both the RLS network and partner distributors with Zircaix being the next prime example of this technology platform.

Two, we have 2 new products to launch, Pixclara, which is known as Pixlumi in Europe. This is for glioblastoma and Zircaix for renal cancer. We understand the disappointment that these did not get approved last year, but this is the price of being at the forefront of innovation in new technology areas.

While people are well aware, it has been a tumultuous period within the FDA itself, we also made certain we took valuable learnings from the experience. We have made extensive changes to the management team. We boosted our regulatory affairs capabilities, and these programs are in good shape for resubmission and approval this year. They are highly anticipated products and will become significant revenue streams, and we have not taken our foot off the gas pedal in terms of market readiness for these products. We are preparing to launch, and I want to make that very clear.

Last of all, we have several very high-value clinical programs. This is not an exhaustive list. In fact, we have over 30 sponsored and collaborative studies running from early stage to pivotal trials. But these are the ones that are going to generate the greatest commercial and financial inflection points this year and are the priority in terms of our resources and R&D investment.

I note that 4 out of 5 of these studies are pivotal or Phase III studies. We have imminent data point coming out on ProstACT Global, which we will take to the FDA to gain clearance to commence Part 2 in the United States. I remind you that the study has already progressed to randomizing patients ex-U.S. for Part 2 of the study and talk a little bit about this later in the presentation.

Our BiPASS biopsy study will complete enrollment this year, and we expect to generate significantly enhanced revenue in 2027 as a consequence of this Phase III study.

Our current late-stage clinical studies pave the way to our first therapeutic commercial inflection point likely in 2028. So these are not distant thoughts. They are all near-term catalysts. And I will come back at the end of presentation to some of the broader sets of upcoming catalysts.

Now Darren, over to you for the numbers.

Thank you very much, Chris. We have today reported a 56% growth in revenue to $804 million. This is in line with our revenue guidance. Notably it's our third consecutive year of double-digit revenue growth. Revenue from Precision Medicine business year-over-year.

Can I just ask, I think that the... [Technical Difficulty]

Please check your mute button.

This year -- sorry, can people hear me now?

Yes, we can hear you.

So this is in line with our uplifted full year guidance. And notably, it's our third consecutive year of delivering double-digit growth -- revenue growth. Revenue from our Precision Medicine business increased 22% year-over-year with EBITDA improving 25% to $216 million, driven by strong demand of Illuccix and the launch of Gozellix.

The Precision Medicine commercial performance permitted Telix to self-fund and derisk our investment into our R&D pipeline and commercial infrastructure to drive future growth. Further, 2025 was a year of significant investment, yet we maintained a solid cash balance of $142 million. We achieved this while exercising disciplined cost management.

Next slide, please, which is Slide 11. Thank you. We've added this slide for our non-account investors. As at a glance, this slide presents the strength of our business model. The left side of the chart shows our revenue sources and their materiality. The middle of the graph highlights our gross margin in the green and that 94% of the GM is generated from our Precision Medicine business. That is approximately $400 million.

As you can see, about half of the gross margin, the red flows om right are invested into our commercial sales and marketing capability, our global supply chain and our corporate functions. But more importantly, flowing right at the top half of the gross margin is approximately $200 million. That's 25% of revenue. And with this, we decide to either invest it in our development pipeline to create future value or recognize it as operating profit. So as business models go, a business that throws off 25% of revenue as operating profit to reinvest in value creation or the bank is pretty damn attractive.

Now moving to our traditional P&L. I've spoken to most of the financial highlights on the previous slides, but will take some time to talk to further highlights. The group's gross margin of 53% remained consistent with the first half performance. We invested $157 million into product development, in line with 2025 guidance and mainly focused on our late-stage pipeline.

General and administration expenses decreased to 12% of revenue from 17% last year, reflecting the efficiencies of scale achieved as the company continues its strong growth trajectory. As a result, we posted an adjusted EBITDA of $39.5 million, in line with market consensus.

Now moving to our next slide. Telix Precision Medicine business is clearly our cash machine. Its financial metrics demonstrate its excellent performance. Precision Medicine delivered an additional $113 million in revenue, representing 22% year-on-year growth alongside a 28% increase in operating profit and a 25% increase in its EBITDA. This demonstrates the high-growth business with capacity to generate significant funds to invest in long-term value creation.

Sales and marketing investments supported the launch of Gozellix, the geographic expansion of Illuccix and the launch readiness activities of Pixclara and Zircaix. As a side comment, if this was a stand-alone business growing at 20% plus per annum on an extrinsic value basis, it would be worth up to 8x revenue. This is a huge value creation for shareholders.

Now moving to our next slide, in Telix Manufacturing Solutions or TMS. We've provided this level of detail on TMS in our half year results for two reasons. Firstly, to give investors and analysts clear visibility into the financial impact of the RLS acquisition; and secondly, to provide transparency into the cost base of the remaining TMS business, helping with financial modeling.

As you can see, RLS delivered positive EBITDA for the first 11 months post-acquisition. At the remaining TMS facility, we increased investment compared to last year to permit us to advance operational activities facilitating clinical and commercial supply. As we now close out the full year of having RLS in the business, we will revert back to reporting TMS as one segment for commercial and competitive reasons.

Now moving on to cash flow. As you can see in this cash bridge, Telix continued to generate strong operational cash flows, which we then invest into our pipeline. In 2025, Telix generated $206 million from operations, enabling the investment into progressing the R&D pipeline.

Excluding our last contingent consideration earn-out payment of $52 million for Illuccix, we produced a net positive operating cash flow of $35 million. I reiterate that our investment into R&D is discretionary and can be flexed depending on our commercial performance, permitting us to effectively manage our cash position. Additionally, Telix utilized cash on hand to support targeted strategic investments such as RLS, ImaginAb, and in our FAP asset. As a result, we ended the year with a prudent cash position of $142 million.

Next slide, please. As we prepare for our next phase of growth, we continue shifting allocation of R&D investment into our therapeutic pipeline. In 2026, R&D investment is planned to be in the range of $200 million to $240 million, with the largest allocation directed to the therapeutic development. This highlights our focus to transition to a high-value therapeutic business. I'd like to take the opportunity to reiterate our investment strategy.

Over the next 2 to 3 years, we expect to grow revenues by advancing assets from clinical development to commercialization, expanding indications and geographic reach. We will invest the funds from this commercial growth into our portfolio and ensure that we have the capabilities, infrastructure, and readiness to deliver on our therapeutic programs.

Our focus will remain on reinvesting revenues back into the business over the next couple of years rather than optimizing near-term earnings per share. We are committed to building long-term value. We believe prioritizing earnings too early can impede the strategic investments required to fully unlock the potential of our pipeline.

Next slide, please. Telix has a disciplined capital allocation approach that is aligned to our corporate strategy, and it has matured a great deal over the last 12 months. We have previously spoken about our 4 areas of focus, and they are investing into our R&D, optimizing our commercial performance, strategic growth opportunities through M&A, and supply chain resilience and production capacity. We believe these 4 areas of focus will underpin our growth long term. We have continued to deliver on our strategy in a disciplined way, ensuring that we have a prudent cash buffer on the balance sheet.

Next slide, please. Looking forward, we see strong momentum heading into 2026 with another year of roughly 20-plus percent revenue growth anticipated. Our full year 2026 revenue guidance is set at $950 million to $970 million, and this is based on current approved products in approved jurisdictions. This range does not include revenue contributions from pending product approvals, which will be incremental. This growth implies up to 25% growth in our Precision Medicine business and a full year of RLS revenue.

Our corresponding R&D investment will be in the range of $200 million to $240 million and will be dependent on the achievement of certain clinical outcomes and development milestones. In conclusion, we delivered another year of double-digit revenue growth, made high-value strategic investments across the business, and maintained a prudent cash position.

Looking ahead, 2026 is set to be an inflection year with numerous important milestones. Our revenue guidance reflects the confidence we have in the business, and we remain committed to disciplined financial management throughout 2026.

I'll now hand you over to Kevin Richardson, Precision Medicine CEO. Thank you.

Thank you, Darren. My first slide, please. Last year, our Precision Medicine portfolio delivered $622 million in revenue, up 22% year-over-year. Importantly, we delivered sequential growth every single quarter. That includes Q3, our most challenging quarter, which was the first full quarter following the expiration of Illuccix transitional pass-through status and the transition to MUC, MUC or mean unit cost reimbursement for a subset of Medicare patients.

Q3 allowed us to see the full impact of that change on the business. Even in that environment and despite ongoing competitive pressure, we still delivered 3% quarter-over-quarter dose growth and 1% sales growth. That performance speaks to our disciplined approach to business fundamentals and the strength of our customer-facing team.

We continue to gain share based on clinical differentiation and operational reliability, our PSMA agents demonstrates fewer indeterminate bone lesions and higher inter-reader agreement compared to F-18 assets, driving confidence in clinical decision-making. We pair that clinical value with highly specialized commercial organization that engages customers every day and consistently differentiates Telix in the market.

Our reputation as an innovator also positioned us for a successful launch of Gozellix. Gozellix was FDA approved in April of 2025, and transitional pass-through status became effective in October, enabling a transitional pass-through supported full launch in Q4 of 2025. We are very pleased with the early uptake and our 2026 full year guidance underscores our strong conviction in the growth outlook for our Precision Medicine portfolio.

Today, we are the only company with 2 PSMA agents on the market. This dual product strategy is a competitive advantage, offering different types of customers meaningful choice across economics and scheduling flexibility while reinforcing our commitment to meeting diverse clinical and operational needs. In short, resilient growth, clinical differentiation, disciplined execution and a platform built for sustained growth.

Next slide, please. What does it take to win in a maturing PSMA market? Winning in a mature PSMA market is no longer about being first. It's about executing at scale. Clinical credibility is nonnegotiable. Products must deliver consistently high image quality, strong inter-reader agreement and reliable detection at low PSA levels across all patient types. Incremental claims aren't enough. Confidence in clinical decision-making is what sustains adoption. Workflow integration matters.

In a high-volume market, solutions must fit seamlessly into established clinical pathways, enable same-day imaging and support high patient throughput without disrupting nuclear medicine operations. Reimbursement sophistication is a competitive advantage. Success requires multiple product strategies that give customers economic flexibility while navigating complex and evolving reimbursement frameworks over extended period of times.

Commercial infrastructure is a must. This is a contract-driven market that demands experienced field teams, market access expertise, compliance rigor, and long-standing customer relationships. These capabilities take a large investment in years, not quarters to build. Supply chain excellence separates winners from participants.

Reliable, flexible dose production and delivery at scale, supported by high service nuclear pharmacy last mile experts is critical. There is no proven shortcut to mass market large volume coverage.

Sustained investment fuels durability, indication expansion, life cycle management and camera technology advances all require ongoing clinical and operational investment to maintain leadership. In short, leadership in PSMA is earned through clinical trust, operational reliability, commercial scale and disciplined investment, not novelty.

Next slide, please. We continue to execute our strategic plan to grow the Precision Medicine business by expanding our product offering, expand our indications on those products and expand the geographies where we market those products.

Global expansion is a priority for Precision Medicine here at Telix. Illuccix is now available in 17 countries with reimbursement secured, and we hold marketing authorizations in more than 24 markets. In 2025, we focus on country-by-country access. In '26, we pivot to driving uptake, particularly across key markets, including the U.K., France, Germany, Italy, and Spain.

In China, we delivered strong Phase III results with 94.8% positive predictive value, including patients with very low PSA levels. We submitted the NDA to the regulators with our partner, Grand Pharma. And with prostate cancer incidence rising and PET/CT infrastructure expanding rapidly, China represents a significant growth opportunity.

While in Japan, our 105-patient Phase III study is progressing well with the first patient dose. This positions us well in the world's second largest pharmaceutical market where prostate cancer remains a leading cause of mortality.

New products and new indications enhance our ability to take share and grow the market and Gozellix is off to a strong start, and we are focused on accelerating commercial momentum in 2026, and you can see that is reflected in our 2026 guidance.

BiPASS is a Phase III study that represents the next wave of innovation, combining PSMA imaging, Illuccix or Gozellix with MRI to improve diagnostic accuracy and potentially reduce or eliminate invasive biopsies. This is about moving earlier in the care pathway, reducing patient risk, lowering system costs, and expanding the total addressable market to include frontline biopsy candidates.

We believe moving to the front line where patients are diagnosed will give us a competitive advantage, both as the lead PSMA in diagnosis, but also in sequential scans that happen later on in the patient journey as physicians want to see consistency scan to scan.

For Zircaix, we've completed 2 Type A meetings with the FDA and believe we have full alignment on key resubmission requirements. We are now focused on completing the agreed deliverables and documentation required for the resubmission. With breakthrough therapy designation, supportive ZIRCON-X data and the inclusion in major international guidelines, this remains a top priority for approval and launch this year. This is a really exciting and highly anticipated product.

Moving on to our neuro platform. We are pursuing complementary submissions in both the EU and the U.S. TLX101-Tx was filed with the European regulators recently, and the U.S. submission will follow closely.

As a reminder, the FDA has granted both orphan drug and fast track designation for Pixclara. Our commercial, medical, and supply chain teams are launch ready. Our expanded access programs serve patients and our customers very well, and they anticipate commercial use of Pixclara.

In short, we built a global commercial platform, delivered successful launches, taken share, penetrated the available market and advanced multiple late-stage assets in high unmet needs markets. We are entering our next phase of growth with momentum and discipline.

Next slide, please. So what does this strategy mean in terms of financial impact? Our current baseline business with some further life cycle management, which we've talked about, should be able to sustain a 15% to 20% annualized growth. This partially reflects the growth of the field overall, as well as our ability to continue to capture market share as the size of the market expands. The recent addition of Gozellix certainly derisked this.

With indication expansion in prostate cancer alone, particularly a major opportunity in the BiPASS study, this growth over the 5 years can be closer to a 30% CAGR. And then when you add in Pixclara and Zircaix, this growth rate defensively looks more like 40% compounded annual growth, especially with metastatic indication expansions that further drive procedural volume.

In short, our current product strategy, which is fully baked from a clinical perspective, just needs to clear a few more regulatory hurdles as it represents future upside for the company. It is a direct consequence of the market presence we are building, the depth of our pipeline and the quality of service we are able to deliver to the patients. This is really an exciting business with a bright future. The growth in Precision Medicine gives us the ability to finance the growth potential of our Therapeutics business.

On that note, I'll hand it back over to Chris, to give you a bit of perspective on that.

Thanks very much, Kevin. Great update, and congratulations on all the success that your team had this year. It was a really remarkable year of accomplishment.

So moving on to Slide 25, please. In a way, this slide is a simplified version of my opening slide, a highly profitable cash-generative business that would garner, as Darren said, a very healthy revenue multiple. It was a stand-alone business, but it's our engine room. And the future growth trajectory of the business will come from how that cash is invested.

Kevin has already shown you very clearly, I think, how the Precision Medicine business alone can grow expansively over the next 5 years based on clinical, regulatory, and commercial inflection points that we expect to achieve this year.

So again, I just want to reemphasize the point that the growth trajectory that Kevin has talked about comes from events that will be completed this year. I think it's also important to reinforce our commitment to manufacturing and supply chain. But in the context of our Therapeutics business, it's more than just reliable and on-time dose delivery. It's about R&D cost and efficiency and perhaps most importantly, intellectual property capture.

We've learned over the last decade that when we use contract manufacturing organizations, do product scale up, that we simply educate the ecosystem in a way that potentially empowers competition, and we no longer wish to do that. So especially, as our therapeutics go into late-stage trials, this has become an important strategic objective of the company.

To be clear, we still use CMOs, but where there's key IP around platforms, targeting agents and certain key isotopes, we are increasingly tackling this in-house or with selected partners.

Moving on to the next slide, please. And this slide shows the reason why. As I've said, Kevin has already talked about what share of the Precision Medicine side of the business we think we can tackle over the next 5 years or so. And on a TAM basis, it's actually pretty conservative. But the therapeutics opportunity is about 3x or 4x bigger for the targets and indications that we are already pursuing. This doesn't even capture the potential for indication expansion into new disease areas that some of the pan-cancer targets we are developing, like carbonic anhydrase IX and FAP can potentially expand into. So it's a really bright future for the theranostics strategy.

Moving on to Slide 27, please. Over the last 5 years, we've built a very strong pipeline with some key disease focus areas, and you're going to increasingly hear us talk about these disease areas as multiproduct concentration areas, frankly, much as we have done with Gozellix and Illuccix on the Precision Medicine side of the business.

Indeed, to tackle some of these major unmet clinical needs, it's going to, in some cases, require a multi-asset approach at different stages in the clinical development or in the clinical patient journey. And so -- and also well-considered combination therapies with standard of care medical oncology. This is evident already, for example, in the design of the ProstACT GLOBAL and IPAX-BrIGHT studies. There are three particular attributes of our pipeline that I'd like to specifically comment on.

Firstly, by taking a theranostic approach, we built a very deep relationship with the referral and prescribing physician in each of these disease areas. This is a competitive advantage, and this relationship depth has already started with our existing commercial product portfolio and will only intensify over the next 12 months. Investors often view the Precision Medicine and Therapeutics business areas as adjacent, but they are clearly not.

Secondly, while we have some very high potential early-stage programs, and this has not exhausted this list because we have a pretty decent preclinical portfolio coming in behind, we have 3 late-stage programs in prostate, renal, and glioblastoma that will generate significant data over the next 12 months.

Based on the current valuation of the company, these programs are essentially a free option, but we think that the data and clinical basis of these programs are very compelling. Most importantly, while 2026 and 2027 financials will reflect the commercial expansion of the Precision Medicine business, 2028 is our commercial launch year for our Therapeutics business. So it's not far away. This is why we have so much execution focus on the [Technical Difficulty] targets, learning about disease extend, exploring new patient populations and ultimately increasing the market size and market share.

For the therapeutics, when they become available, the Precision Medicine business will pave the way. And so notwithstanding a few challenging but also educational regulatory speed bumps we've had, our commercial imaging gives us the skills and confidence that we can deliver on the therapeutic programs in the future. We've learned a lot this year, especially last year.

Can you hear me, okay? All right.

Moving on to the next slide, please. As I noted earlier, we have many different clinical studies running, some company-sponsored, some in collaboration with key opinion leaders around the globe. But the 4 major trials to watch this year are outlined here. I'm not going to go blow by blow on these because this is an earnings call, but I think it's important for shareholders to understand where the research priorities are and what the development goals and catalysts are. We are collecting a ton of patient data this year, and it's very exciting to have 3 programs in pivotal studies. This is important for patients and important for shareholders, and it's taken a lot of work and investment to get here.

Moving on to Slide 29. Of course, front of mind for patients and shareholders alike is the ProstACT GLOBAL study. The study is now recruiting into Part 2 randomized part of the study ex-U.S. and is ramping up very nicely. Unlike Part 1, which is a safety dosimetry run-in study that the FDA required in order for us to include U.S. patients in the randomized part of the study, Part 2 is very streamlined and straightforward. Part 2 commenced recruitment last year following an independent data safety review that determined that Part 1 data met prespecified safety criteria to progress. We will be shortly releasing the details of the Part 1 study concurrent with our submission to the FDA to request approval to add U.S. patients into the study. We are looking forward to getting these results out into the market and to show the great progress we are making, particularly given the unique combination therapy design of the ProstACT GLOBAL study.

To remind you, the data we will be putting out from Part 1 will be safety data on the 3 standard of care combinations in the global study, as well as comparative dosimetry data, which will be very interesting to see, particularly for the 2 different androgen deprivation therapies used in the study. So this is coming soon.

Moving on to Slide 30. Before I wrap up with a summary of the catalysts, I thought I would share a montage of patient case studies to really tie together the company's strategy and to illustrate how integrated the Precision Medicine, Therapeutics, and Manufacturing businesses are.

In short, why we are here. This slide illustrates 4 patients in 4 different cancers, all of which are advanced, extremely difficult-to-treat cases. Every day across the entire portfolio, we see examples of where our development and commercial pipeline changes lives. Sometimes it's a better understanding of the extent of disease. Sometimes it's a profound disease modification, such as the metastatic prostate and breast cancer examples on this slide. And at times, it's the glioblastoma or the kidney cancer patient that has stabilized disease or enough reduction in pain to be able to return to work.

These are the real outcomes from our research, and they deliver profound and life-changing outcomes for patients. This is what motivates us and why we believe that investing our hard-earned cash into this future is so important. The technology works and will get better as we learn more and get more clinical experience.

I'm also obliged to point out that for the most part, what you're seeing here are images created with the companion diagnostic imaging agents that we are also developing and highlights that this -- that not only is imaging technology critical for diagnosing and staging patients, but will play a fundamental role in predicting and measuring disease control as well.

Moving to the last slide. To wrap up, this slide summarizes the year ahead. It is a big year with many inflection points across the entire business. I will not go line by line, but we have a lot to talk about in 2026, with the next 3 major catalysts being resubmission of Pixclara and of course, Zircaix and the release of the Part 1 global data. We are looking forward to delivering these important milestones to patients and shareholders as the year progresses.

With that, I will pause and hand it over for questions.

[Operator Instructions] Our first question comes from Laura Sutcliffe with Citi.

At the risk of potentially making myself a bit unpopular, I think we'd like to understand a bit more about when we might see some data for 591, the safety data. And perhaps given that you said you will disclose at the same time that you go to the FDA, whether the next steps are things that you need to do at Telix or whether you're waiting for the FDA to do something on their end to be able to get to that point?

Laura, thanks for your question. It's not a bad question or an unpopular question at all. So we have had an independent data safety review board that has under the clinical charter of the study has reviewed the data and progressed to randomization ex-U.S. However, in order for us to send the information to the FDA and disclose the information publicly, we need just to complete the clinical case report forms and formally close out and quality control and validate the data because that's obviously what the FDA wants to see. As soon as we have that data -- and I haven't seen it, I'm not privy to it. But as soon as it's available, we will simultaneously disclose it and submit it to the FDA. So we're not waiting on anything from the FDA. It's all on the company side, and you will not have long to wait.

Our next question comes from Tara Bancroft with TD Cowen.

This is Nick on for Tara. Congrats on the progress and the strong guidance for 2026. We were hoping that you can dive in a little more on what you've seen in the early innings of the 2-product strategy for Illuccix and Gozellix and how you anticipate that will evolve this year to reach the 25% growth in the precision medicine revenue?

Yes. Thanks very much for the question. Kevin, do you want to pick this one up for your wheelhouse?

Sure. Yes. Thank you for the question. So the 2-product strategy is -- enables us to really manage the economic needs of HOPPS accounts and the way that they perceive and their preference for a reimbursed product over really a non-reimbursed product.

As you know, MUC or Main Unit Cost has really kind of changed the environment and the reimbursement environment there as well as the way that the pricing happens in the HOPPS accounts. So being able to have a 2-product company enables us to manage that particular customer type and the self-standing -- or we call them IDTF group -- in a different way as we manage the preference they have for a reimbursement price or one that might be a little more price sensitive.

So and then, of course, we have a longer view of the precision medicine business and PSMA specifically, as we think through what over time can happen and what will happen with CMS as they continue to evolve and change reimbursement. So that enables us to kind of manage the ASP, if you will, as the CMS may or look more towards the ASP reimbursement model. So it gives us options in the future without locking down a singular product on that.

Our next question comes from Shane Storey with Canaccord Genuity.

Kevin, I'm going to stick with you, if that's okay. Question on Pixclara. Just maybe some descriptive piece, I guess, around the customer channel there. It's quite different from your PSMA urology presence. Is that potentially a first work example for how the Varian relationship might evolve? Just some thoughts on that, please.

Kevin, are you there?

Yes. So I'll take that first then, Chris. So Varian is -- we're really excited about the possibilities in that, a lot focused, of course, on PSMA and Illuccix, Gozellix. And so as we think about that from a commercial perspective, we have a -- what we call a Ninja team.

As you know, there's not as many sites as there are that do PSMA prostate scanning as there are that are going to do neuro scanning. So we have a smaller team that's focused on the referral, the neurologist. And the idea behind that is we already have the relationship at the NucMed level. So we're able to drive those patients into the scanner, if you will. And then we have a team that already has the relationships at the other end of that where they're reading it. So the idea is it's a referral and then into the existing relationship we have at the nuclear medicine side. And of course, if that is not an Illuccix or Gozellix site, it gives us good access into those sites, and it's a real competitive advantage to be able to offer these more orphan drug type technologies because of that.

Does that answer your question, Shane? Okay. Chris, anything to add?

All right. No, that's good.

Our next question comes from David Stanton with Jefferies.

I might be following a dead horse here, but I just want to make it clear and help you to make it clear. You'll be reinvesting earnings to get close to 0 NPAT for F '26, F '27 and F '28. Is that what the market should be thinking going forward, please? I ask because it's a question I get asked the most.

Yes, that's fine. No horse is flogged, David. Happy you asked the question. So we're not giving guidance beyond 2026, but it's a reasonable expectation that in 2026 and 2027 that we will be investing -- other than for risk management and for appropriate balance sheet management purposes, we'll be investing the majority of our earnings back into the company, okay? So that's in a number of different areas. That's in R&D. That's also in growing and developing our commercial team. And of course, we continue to also invest in infrastructure and capital works to support the business.

So it's not all just R&D, but a profit objective for this year and next year is not the name of the game.

Our next question comes from David...

Do you have a further comment, David, that you'd like to ask? All right. Well, we'll move on. This is a very challenging conferencing service, and I apologize to those that are participating.

It's a follow-on from Dr. Stanton's question. Just from Darren, there was a clear comment there that I think that the investment in growth will consider the commercial performance. I think that was interesting from our perspective. Just as we look at the sales guidance for '26 and the R&D guidance for '26, should we think that if the commercial performance is at the upper and lower end of those ranges, the R&D will follow?

As an extension of that, within the R&D spend, is the earlier stage clinical trials, are they the ones that would potentially be put on hold for a little bit to the extent that the commercial performance doesn't meet expectations?

I can start, Darren, and then maybe if you want to add anything. I mean -- so yes, we've focused -- we've chosen in this presentation to highlight the clinical studies that are the real priorities for the company. So that's the 5 studies, including the BiPASS study. We are obviously going to be investing in other clinical studies this year. And to the extent that we need to make adjustments -- it will be outside of that sort of ring-fenced 5 studies, the 4 therapeutic studies and the BiPASS study.

We clearly expect that 2026 is going to be a strong year. We don't expect to have any difficulties in financing our R&D pipeline. But as you have noted, and as Darren, I think, made it very clear, generally, we take the view that our R&D investment is discretionary, and we can make adjustments as required.

Darren, do you want to add anything? Okay. I'll take that as a no.

Our next question comes from Craig Wong-Pan with RBC.

Just a question on the 25% growth in Precision Medicine. I was wondering how much growth was coming from markets outside of the U.S.

Sure. I'll answer that one and then maybe, Darren, if you want to chime in on anything that I've missed.

Right now, because we only achieved our European reimbursements towards the back end of last year, it's a very small proportion of the revenue is currently ex-U.S. The majority of it is -- 95% of it is U.S.-based. We obviously expect that mix to change over the course of this year and also as we add in other markets, such as Japan, which has a high-value PET -- advanced PET procedure code that's quite internationally competitive. But for the moment, for the most part, the majority of our revenue is U.S.-based.

Our next question is coming from Andy Hsieh with William Blair.

Chris, I want to ask you about the recent collaboration with Atley and Stanford, focusing on astatine-211. So in your pipeline, you have 3 alpha emitters: Actinium-225, you have lead generator that's in progress, and then now astatine having a California supply chain. So I'm curious about your view on this isotope, another short half-life. Just wondering about how it fits into your product portfolio.

Yes. It's a bit of sort of outside of the major sort of activity area. But essentially, we do see value in alpha emitters. The majority of our late-stage programs, as you know, are beta-emitting isotopes. We think that they're going to be a workhorse for the foreseeable future, but we can see ALPHIX coming over the horizon.

As you know, most of our clinical stage programs are with actinium. It's probably from a supply chain perspective, the lowest hanging fruit. We have one program, TLX102, which is with astatine that's in early clinical translation. We think that for applications where a targeting agent needs to cross the blood-brain barrier that radiohalogens are a better perhaps a more practical pathway than a radio metal with a chelator. So we are exploring astatine mostly in the CNS setting.

Then we do, as you know, have a lead generator that we've developed. It's a very novel and very compelling generator design that we think can be rolled out for large-scale lead production. We currently today do not have any clinical programs using Lead-212, but we have a number of preclinical programs that we expect to take into patients by the end of this year that are not currently disclosed, and they have the potential to use Lead-212.

We are exploring several different isotopes. But I think as a company, we've elected to put a proportion -- not a large proportion, but a modest proportion of our R&D expenditure into understanding the future landscape of alpha because we think it has some potential. I hope that answers your question.

Our next question comes from David Dai with UBS.

Just on the gross margin for the business, it seems like it's remaining stable at 53%. But then the RLS business, the gross margin has been quite poor. So just thinking about the gross margin for RLS business moving forward, what are some of the key drivers of gross margin expansion for the RLS business that you can provide?

Well, I'll just make a comment, and then I'll invite Darren to chime in. So the RLS business -- so just to be clear, when we report the RLS segment, we report the RLS segment purely in terms of third-party products. So these are not Telix products. These are, for the most part, fairly generic nuclear medicine products. And RLS' operating cost is largely covered by delivering those third-party products.

So a useful way to think about it is as a subsidized -- third-party subsidized manufacturing infrastructure. When we report the products that go through the RLS network that are Telix products, they are captured in the segmental reporting for precision medicine. So I just really want to make that very clear.

So when you say the gross margins for RLS are not very good, it's got nothing to do with Telix's product portfolio. RLS margins -- because these are generic sort of fairly commoditized nuclear medicine products, they have a much, much lower margin.

We provided an average margin last year, which I think frees a lot of people out because all of a sudden, we went from mid-60s margins down to mid-50s margins or low 50s margins. That was an average effect across all of the products in the group, including the RLS products. Does that make sense?

Yes, that makes sense. Yes.

So yes, so don't be sidetracked by RLS. The most important thing is that when we put our products through RLS, we -- that gross margin number, which we report faithfully for the Precision Medicine business as sort of mid-60%. That's our -- that above-the-line cost is our distributor margin, which clearly is different when we run a product through our own pharmacy network.

Now it's critically important for us to maintain key distribution partnerships in key markets. So we obviously, do pay that above-the-line cost. But when we produce a product that goes through our nuclear pharmacy network, the gross margin is rather different. So you should expect to see, as we have a larger share of our product volume going through our in-house pharmacy network that, that gross margin number has the potential to improve and trend towards 70%.

Our next question comes from Andrew Paine with CLSA.

Maybe one for Kevin, but you mentioned winning in the PSMA is about executing at scale, and we've seen that in the growth and the challenges you've overcome in that market so far. You spent a bit of time talking about this, but how clear is it that moat -- how clear is that moat there for you given the potential competition on the horizon? And also, can you just dig into the changes in camera technology and how you see that as supportive to the sensitivity of PSMA imaging, which may not be fully appreciated?

Well, I think Kevin has done a great job of running through what the competitive barriers to entry, and there are multiple. I mean it's not just product, it's also clinical, it's also manufacturing and supply chain. So I'm not sure what competitor you're talking about that's coming immediately on the horizon. But nonetheless, we see those as, I mean, pretty well enumerated sort of barriers to entry for competition.

On the topic of camera technology, generally speaking, we've seen a step change in sensitivity on PET cameras over the last 3 to 5 years because of the demand for PET imaging, not just in prostate cancer, but across a whole lot of indications, including neuro-oncology, neurodegeneration, cardiovascular disease. We're seeing a lot of camera installation going in and the next generation of scanners are in order of magnitude more sensitive. And so that just means that we have to keep abreast of it.

We need to make sure that we're running clinical trials and clinical studies that demonstrate the improved utility. We are clearly detecting disease early and earlier. I mean, we have our most recent studies that were done in China, for example, with absolutely state-of-the-art scanners because they're brand-new scanners. We're seeing PSA levels down to fractions of a nanogram per ml. And so the camera technology is part of the complementary story to Tracer development that should not be forgotten about. I think I'll pause there in terms of that particular topic. There isn't too much more else to say. Is there another question?

Our next question comes from Melissa Benson with Barrenjoey.

So Kevin mentioned you had a full alignment on the agreed deliverables with the FDA for the...

Melissa, I'm sorry, I can't hear you. Now I can hear you. Go on.

I'm sorry. So I think Kevin was mentioning there was alignment on the agreed deliverables with FDA, [ per the K ]. So I was just wondering if there's anything you can share regarding what those agreed deliverables are, but specifically, if there's any new clinical data required or if it's more preclinical analytical data only?

Yes. Most of the CMC remediation topics are around laboratory documentation, manufacturing documentation and process documentation. We do have a deliverable to the FDA around comparability between the research grade material that we used in the Phase III trial and the commercial scale-up material. But we have that data set well in hand, and it's not a material time delay to the resubmission.

Our next question comes from Steve Wheen with Jarden.

It's Steve here. So my question was just a bit of an extension of some of the others. But I guess for Kevin, I'm just trying to understand the European market with regards to Illuccix and Gozellix, I guess. Just they've been approved for some time. The launch in the U.S., obviously was incredibly rapid. And just trying to understand what's holding it back or slowing it to not really be much of a feature for your growth in the next 12 months?

Kevin, I can start and then maybe you can finish. I mean, it's not that it's not a feature. It's just that the European market has a very different reimbursement landscape. The U.S. has a much more immediacy between product approval and reimbursement, whereas in Europe, sometimes there can be as long as 9 or 12 months delay between product approval and reimbursement. And there's simply no material product sales until you have reimbursement. It's also not a class reimbursement. It's an individual product reimbursement in most countries.

So until you have reimbursement, you simply don't have material sales. So for the -- what you would classify as the traditional EU 5 countries, we have only just received reimbursement in some of them.

Kevin, I don't know if you want to add anything there?

Yes, there's very little other color to add in my prepared remarks, which was really 2025, the international team under that direction was really focused on gaining market access through reimbursement. And now we in that EU 5, the plans now are to execute those market launches. And so you'll see that as we continue to grow in 2026 as we execute against that launch. But Chris is right, in each country is different, each product is different. So it takes a bit to get that approved in the system and then begin the launch. So we're in the midst of that right now.

Can I just ask an unrelated question just with regards to your R&D the expensing of Zircaix through the R&D line, is there a shelf life for that particular inventory just with regards to just noticed your comment that there is the potential once it's approved by the FDA that, that could then come back and be backed out of the P&L?

Yes, that's right. That's our expectation. And the shelf life goes far beyond the launch time of the product.

Our next question is a follow-up from Shane Storey with Canaccord Genuity.

Sorry for extending the time, everyone. My question was going to come off the back of Melissa's question actually on Zircaix and except everything you've just said there. But just as far as how we should think about FDA's review phase once the resubmitted BLA is accepted, we've been sort of assuming 6 months. I just unsure how the breakthrough status and priority review might influence that, if at all?

Yes. We don't know yet for Zircaix. For Pixclara, we have a reasonable idea that it's going to be a rapid review also because it's a single a single issue CRL. We could imagine for the Zircaix review because there is a number of issues that it may take longer, but we haven't received guidance yet from the FDA on this topic.

We will be engaging with the agency shortly on this topic as we are preparing to resubmit, but we won't know that information for a little bit when it comes to Zircaix. No worries. But I do note that it has a breakthrough designation. And I actually want to compliment the agency. They've been highly engaged, very helpful, very proactive. They gave us a lot of extra time around the Type A meeting that they really didn't need to do.

So we feel like it's a pretty good collaboration, and we're working with the agency towards the drug approval and nothing less than that.

Okay. I think I have a feeling that we're wrapping it up there. I don't know if there's any more questions coming through.

We do have a final question, a follow-up from David Stanton with Jefferies.

Saving the best for last. Chris, just I note that you've talked to a Part 2 interim analysis in calendar '26. I wonder if you could sort of give us any kind of timeline as to when that might be? Is it third quarter? Is it fourth quarter? What should we be thinking there?

Yes. Obviously, I get increasingly reluctant to estimate timelines on clinical trials because [Technical Difficulty] by like to the day or to the week rather than to the quarter. But right now, the Part 2 study is recruiting really nicely. We're seeing good site expansion and getting plenty of patients consented into the study. That interim analysis is based on about 80 or 90 events, I don't know the exact number, sometime -- somewhere around that. And we would expect that, that should lead based on the current recruitment trajectory for some time in Q4 of this year for that futility analysis to read out. So that's the reason why we have it sitting there in the calendar for this year.

Well, I think that was the last question. I just want to apologize profusely to all the attendees for the audio challenges we've had today. It's a new conference provider. I'm not sure we'll be using it again in the future. But I just wanted to thank you for your questions and for your attention.

Obviously, if there are follow-up questions, we'll be happy to receive them directly and follow up in due course. Thank you for your time today.

This concludes today's conference call. Thank you for participating. You may now disconnect.

Okay. Good morning. Thanks for joining us here at the JPMorgan Healthcare Conference. My name is Chris Cooper. I cover Australian health care here at JPMorgan. For this session, we're very fortunate to be joined by Christian Behrenbruch, the CEO of Telix. Chris will speak for about 20 minutes or so, and we should have some time for Q&A at the end.

Well, thanks very much, Chris, and to the JPMorgan team for the opportunity to present. Just the customary disclaimers and forward-looking statements. So for those of you who don't know, and we're an increasingly well-known company in the radiopharma space. I know there's a lot of folks that are starting to take interest in the company and its commercial trajectory. We're a fairly vertically integrated radiopharma company specializing in oncology. We are solely focused on radiopharmaceuticals. We have a very much a precision medicine-oriented approach in the way in which we think about radiopharma.

A lot of new companies have emerged in recent years that are focused really just on the therapeutic aspects of radiopharmaceuticals. But if you think about what you get when you develop a radiopharmaceutical, you get a signal with every dose that you put into a patient. And that signal is extremely valuable in terms of understanding the efficacy and the targeting the delivery of your payload. So for every target that we develop as a company, we develop both an imaging agent and a therapeutic.

And this has actually served the company well from a commercial strategy perspective because we've been able to monetize that precision medicine business early in the company's life. So we are a commercial stage company. We've built a very capable commercial team. In fact, I think it's one of the great assets of the company. And certainly, from a commercial execution perspective, the last 12 months have been very successful for the company. I'm going to go into a bit of detail on our therapeutics pipeline. That's going to be more so the focus of this presentation, a little bit on our new capabilities around basic R&D.

When we founded the company almost a decade ago, we didn't really have the appetite to do discovery or new asset development internally. But we now see that there's an opportunity for us in some key areas, and I'm going to give you a bit of insight into that as well.

And then last of all, one of the things that differentiates Telix very much from other companies is the commitment and the investment that we've made. We've invested about $0.5 billion in the last 2 years on manufacturing, supply chain, distribution capabilities. We own a nuclear pharmacy network in the United States, which we think is very important to future distribution of therapeutic radiopharmaceuticals. And that vertical integration really sets us apart from competing organizations. So it's a very full story.

Our lead commercial product is in the prostate cancer space. Actually, we have 2 products, Illuccix and Gozellix. Gozellix is a life cycle management product for Illuccix. It's been a very successful product launch. We are now -- and 2025 was an extremely busy year for the company. We expanded into 17 other countries outside of the United States, including Europe and the U.K. and also, we have an approval in Brazil.

We are -- we filed an NDA now in China, and we have a Phase III study, active, a bridging study in Japan, which will complete this year as well. So really, our goal as a company, and again, it's a little bit different than some of our peers is to really be globally active. We think that, that's important. And again, the precision medicine paves the way for a therapeutic presence in these countries.

As we look more and more clinical practice guidelines, patient selection and patient stratification through imaging is how we deploy radioligand therapy. And so having that footprint in these other countries is not just about generating some early and important revenue streams for the company, but they're also about establishing that physician presence and that customer relationship.

Gozellix was a great success for us last year. So we got a new drug approval back in April of last year. We got pass-through for this product, which became effective 1st of October. So our last -- this past quarter was our product launch quarter. We had a really nice quarter. We'll be putting out our financials next week around the middle of the week, and you'll be able to see what the impact of that is.

But again, this is -- it was a life cycle management with some really nice differentiation in terms of how we deploy the product, how we are able to reach patients that are perhaps further away from major metropolitan areas but also much larger capacity production really into the hands of those academic centers using our cyclotron technologies capabilities, and I'll maybe talk a bit more about that later on.

Financially, this is a snapshot of the company's growth over the last 5 years since we became a commercial stage company. I really do think that the commercial execution is something that we've done extremely well. Our guidance for the full financial year is in the USD 800 million to USD 820 million range. We expect to see this growth trajectory to continue over the next -- really over the next 2 to 3 years. It's not just about our prostate cancer imaging franchise. It's really about how we have layered in multiple products that are coming online very soon that are targeted at really building that deeper relationship with specific referral physicians that we have a strong level of traction with, particularly in urologic oncology, and I'll talk a little bit more about that.

So we also -- through our radiopharmacy business, we have a certain amount of third-party revenue. We've actually continued to grow those volume really nicely in that part of the business over the last 12 months. So it's been a successful acquisition, although quite demanding on the organization. We went from about 350 people at the start of last year to almost 1,200 people at the end of the year. So we introduced a lot of capability but we also organizationally matured a lot last year. And I would say that with some of the setbacks that we had last year, which are reflected in our market cap, we really went back. We reengineered the bench strength in our development teams. I think we really augmented our capabilities.

And I feel that 2025 is a bedrock year that we can really build on in a very promising way in 2026. So in terms of growing the commercial near-term revenue-generating part of the business, there are sort of 3 parts to the strategy. Pixclara and Zircaix, NDA and BLA resubmissions are proceeding as we expect them to. Pixclara will be submitted very shortly. Zircaix is well on its way. We've got one more FDA meeting coming up, and then that will follow Pixclara. We've generally had a very high degree of engagement with the agency. So I feel like those resubmissions are in good hands. And we do expect to launch those products in 2026, obviously, subject to regulatory approvals in the United States.

We do have plans, of course, to expand other geographies as well as we did with Illuccix. The 2025 for Illuccix was really about getting those marketing authorizations and getting reimbursement moving outside of the United States. We expect to see the financial contribution of that in 2026 or at least start to happen. And as I said, we do have a plan for follow-on registration for Pixclara and Zircaix as well outside of the U.S. That's very much in play right now.

The other thing that we're working on is really expanding the indication in our existing prostate cancer franchise. So we -- prior to Christmas, we launched the BiPASS biopsy study, which I'll talk a little bit more in a second. This is really a game-changing indication expansion for prostate cancer that we think will significantly increase the total addressable market for Illuccix and Gozellix. And again, it's part of our longer-term growth strategy as a company.

The PSMA market itself has a lot of headroom. We see today that it's about a $3 billion TAM. We're a significant player in this. We have now doubled down in terms of our presence in this market segment with Gozellix. We see opportunities just through practice guidelines and continued clinical adoption to expand the market. We see BiPASS as a potential part of that. And then we have a long-term life cycle management commitment.

So we have several other follow-on products. I think it's now accepted in the industry that some -- like other parts of pharma, that regular life cycle management of these diagnostic imaging products are going to be important for maintaining commercial leadership. We have a very clear game plan for how we're going to do that, including picking up some capability in the fluorinated PSMA space. We have a Phase III study that will launch this year based on a very novel approach to flexibly radiolabeling PSMA11 with either gallium or F-18. There's a physician choice there. We're happy to serve that choice in a flexible and differentiated way.

I did mention the BiPASS biopsy study. So this is really about going upstream from the current label space we have in prostate cancer imaging. The majority of patients are either pre-prostatectomy high-risk patients where you're looking for extra pelvic metastases or patients that have reoccurred following a definitive intervention and have a rising PSA. We believe that biopsy is something that can be optimized. We're not looking to eliminate biopsy. What we're looking to do is to make sure that when a patient gets biopsy that they are the right patient for a biopsy. There's more than 1 million biopsies that are performed in the U.S. every year, really only about 20% or 30% of those are actually beneficial to a patient.

So if we can triage that, that's very powerful. It's got a clear pharmacoeconomic benefit in terms of patient impact and diagnostic impact. But what it also does is it positions us very much at the front of the queue. We're going to be there at the beginning of that patient journey, and it puts us in a position to repeatedly serve that patient over their prostate cancer journey over the course of their life. And I think that's not just a clinical advantage, that's a commercial advantage as well.

So this is a Phase III trial. It took us about a year to get it over the line with the FDA. These kind of very early-stage intervention-driven studies are extremely clinically challenging to get launched, a high degree of regulator buy-in to get a label forming study all over the line. We've now done that. It's actively recruiting internationally and in the United States. So I'm really excited and recruiting very fast. This is going to be a very quick study for us to get done.

Just maybe a little bit of comment and build on my earlier comments about scaling globally, really over the last 3, 4 years, we've built a pretty impressive international footprint in terms of our ability to deliver product. This is not just for diagnostic products. This is for therapeutic products. So this includes GMP manufacturing capabilities in the United States and Europe, and we're increasingly building capabilities in other parts of the world as well.

We just opened our first production center in Japan which is a commercially important market for these products late last year. And we have a couple of key partnership relationships as well in Latin America, where we do do manufacturing in a joint venture and also in China, where we have a regional strategic partner. So very active global footprint, and part of the investment that we made in buying radiopharmacy infrastructure was really to acquire that step change in scale function for the company.

We delivered 150,000 Illuccix doses and Gozellix doses last year in the United States, either through our own pharmacy network or with key partners, long-term partners, like Cardinal Health. In totality, the group delivered about 2.9 million doses to patients last year across all of our operating segments. This is really about building a foundation for long-term volume growth and delivery to our patients. So I think the commercial execution and the manufacturing and supply chain execution for the company has been very strong and is getting stronger every single day.

In terms of the investment strategy, so it's useful to think of the company really in terms of kind of 3 epochs. 2025 was a transitional year for us where we really started that large-scale reinvestment phase for the company, which is the sort of middle period. We had our initial commercialization. Our first product approvals, now it's really about diversifying that revenue stream to multiproduct and regional expansion. But the goal between now and the end of 2027 is not an earnings-oriented goal. The goal is to really take the revenue that we generate from our commercial business and maximally reinvested into pipeline and infrastructure.

We're very blessed. I mean, we're butting up to $1 billion in revenue. We expect to significantly exceed that over the next couple of years. It gives us enormous earnings capacity in a nondilutive way to reinvest in the business. And we're doing that extremely assertively. So we're trying to set expectations with investors and analysts. This isn't an EPS story. Even though we are classified as a health care company, a lot of people see us as a health care company. We're really a self-funded biotech company that's doubling down and tripling down on our pipeline and our supply chain capability.

So the next 2 years are going to be really exciting in terms of building that infrastructure, building out that pipeline, and we have 3 therapeutic programs that are in Phase III pivotal late-stage trials this year that starts to build a ton of value creation for shareholders as we get new data points come out.

Once we get into 2028, that's where we expect to see our investment needs outstripped by earnings. And then I think maybe we'll look more like a regular health care company at that point in time. But right now, it's -- think of us as a self-funded biotech company. And I think that's a -- I think it's a very powerful position to be in given the market dynamics that we experience.

I did mention in my opening comments as well, a little bit about our interest in being a little bit more of an in-house innovator. This was something, speaking as the founder CEO of the company. I was never really that keen to do. I felt that there was lots of great innovation being done in academia and small companies. We can be a channel partner and a go-to-market partner for that. But what we're seeing now is the emergence of all kinds of exciting new isotopes. And if you look at the products that -- I like to think of them as first-generation radiopharmaceutical products that are out there that are either very unoptimized small molecules or they're somewhat unoptimized macro molecules.

And actually, as we see things like lead-212 and actinium and astatine come forward, there's a real desire to match the pharmacology of those targeting agents with half-life of those isotopes to build products that have better efficacy, better patient tolerability. And so we've decided that alongside in-house isotope research and cyclotron technology development capabilities that we are also going to develop a biologic centric innovation capability to look at some of these formats that are in the middle of the PK spectrum where there are hours to day, blood half-life where they match very, very well on to some of these next generation of radionuclides that are coming down the pathway.

And we've got 2 really exciting programs, 1 in DLL3 and 1 in [ avß6 ] integrin binding domain, which are getting ready to go into the clinic so by the end of this year, they should be ready to go into person human studies with alpha-emitters extensively

Okay. So just as a wrap up before I go into a couple of snapshots. I'm not going to go exhaustively through our pipeline, but just to spend 5 minutes or so going through some key examples. This is our late-stage therapeutic -- or clinical stage therapeutic pipeline. So this does not include a number of assets that we are developing preclinically. So everything that you see on this list is being administered into patients today or has an IND approval to go ahead. So it's a pretty substantial pipeline of assets. Notably, our TLX591 prostate cancer therapy is in Phase III. We've completed a run-in study, which we'll read out very, very shortly, and we are already recruiting ex U.S. part 2 of that study, so the randomized portion of that study.

We also have a go ahead for putting our Carbonic anhydrase IX program into a Phase III study as well as our [ IDIN ] 131-based glioblastoma agent, which has shown some promising efficacy. And I'll go into a little bit more detail on second. I think just as a general comment about our pipeline, 1 of the things that you'll notice is that we are not a platform technology based on a single radionuclide. That's not how cancer works. We don't think that's how radiopharmaceuticals will be developed, we think that it's really important to choose the right isotope for the right application, the right -- it has to be aligned with the biological problem that you're trying to solve.

And so that's 1 of the reasons why we have invested and built such a strong in-house capability on the basic radioisotope and isotope sciences part of the business to be able to facilitate that diversity of decisions around our isotopes.

Okay. So very quickly, just a couple of key snapshots. I'm not going to go exhaustively through the whole pipeline. As I mentioned, our 591 asset, which is an antibody-directed PSMA therapy or radio ADC, as we like to call it, we have completed a run-in study, which was something that we agreed with the FDA as part of our new manufacturing package. And we have Part 2, which is the randomized segment of that study is already recruiting in a bunch of countries outside the United States, Australia, Canada, U.K., Turkey, Singapore as a whole raft of 7 or 8 countries that are already recruiting.

We are shortly going to be disclosing the Part 1 of that study, although I note that data safety review has already taken place of Part 1 to enable Part 2 to move ahead. So we see this as a fairly straightforward process from a disclosure and an FDA engagement perspective, and that will happen in the very near term. We've seen historically really good data with this asset. It's highly differentiated, we inject a much smaller amount of radiation into the patient. We have a very condensed dosing schedule. That's 2 shots, 14 days apart. We have a very differentiated clinical utilization in terms of -- we don't need specialist infrastructure. We don't need radioactive toilets. There's a lot of things about this asset that make it very nice to administer.

And we get really positive feedback from the key opinion leaders that use it. So I'm excited to see a real push this year on completing that randomized Part 2 and hopefully continue to get this sort of data that we've seen historically, which is very, very encouraging from product differentiation perspective.

Our follow-on program in alpha, TLX592. We did a study with a proxy to Actinium, what we have seen in other assets, for example, with the JNJ KLK2 data is that assets that have a long circulation timing of blood tend to have -- and where you have highly perfused organs, like, for example, the lungs, you tend to see adverse events with alphas. We wanted to make sure going into our first actinium program that we understood the biology and the pharmacophore that we're using very well.

And so we did an imaging study first, a nontherapeutic study to really look at biodistribution and to feel confident that we had something that was the right pharmacology to take into patients. It was a very, very slow because it's an imaging study. It doesn't confirm much patient benefit, but very enlightening. It enabled us to set mass dose, it enabled us to design our first-in-human study with Actinium that has now received clearance to start clinical trials, and we're in the process of recruiting first patients into that study.

So I'm really looking forward to seeing that story evolve, it's our first true alpha program and very, very differentiated approach for targeting PSMA with an alpha-emitter. We are looking holistically at our therapeutic landscape in prostate cancer. We are interested in earlier stage disease. We look at that through the lens of the alpha program. We look at that through the lens of our collaboration, for example, with Varian and looking at how you do image-guided SBRT in early-stage patients. I think there's a real role there for the combination of external beam radiation and endo radiotherapy together, is that something that we're really looking at.

If you look at the prostate global trial, our Phase III trial, it's a mixture of first-line and second-line castrate resistance. So it's in that sort of middle of the treatment journey.

And then TLX090 is really at that end-stage journey. We see a prescriber appetite for radiopharmaceuticals in advanced patients. The art of palliation in nuclear medicine has been somewhat lost because of successive product cannibalization. So there's an opportunity to go back in there and really reestablish nuclear medicine-based palliation but with a next-generation product that has a lot better economics and a lot better patient safety profile. This is a really exciting asset, and it has huge patient impact. So a lot of patients -- a lot of prostate cancer patients that reach the end of their hormone therapy and their PARPs and their radioligand therapy. They don't have other treatment options. They go into palliation with a lot of pain. This is a really important opportunity to serve the patient going into that transition to palliation.

So we're getting our -- is basically a bridging study to a traditional samarium-based agent. It will give us a good understanding of how we stack up against historical agents in this area. And again, that program is getting really nice momentum with key opinion leaders that are involved in the study.

I mentioned in the beginning that 1 of our strategies is to really double down and that's with a particular referral physician. That's not just on the diagnostic and imaging side, but also on the therapy side. So we do have nice Phase I and Phase II data in clear cell renal cell carcinoma. We have the LUTEON trial now, which is up and running, it's a Phase II/III trial. It's really about a fast run in dose finalization into a Phase III trial. That's a key execution focus for us this year with the new TLX focus on real clinical execution and timely clinical execution. So we expect to really get a good data momentum there in this program this year.

We've seen nice examples of targeting. We've seen some really interesting patient examples where this asset has made an impact on patients. And so we've got a lot of expectations at this program, it will yield good outcomes for the company over the next couple of years.

And then just very quickly, outside of uro-oncology, our IPAX BrIGHT Phase III trial has started a pivotal trial. This is, again, an adaptive dose optimization leading into a primary label registrational study, it builds on what we've learned in the IPAX-2 study. So we really have a clear understanding of the dose range that this thing works well at, very good understanding of the patient safety profile. We've seen excellent evidence of any tumor effect in the studies that have been performed to date, some of which has been published recently in peer review environment. So it's really, again, a very exciting opportunity for the company that will generate quite a bit of momentum this year in terms of late-stage development.

And then finally, just 1 other call out, as I'm running out of time. One last call out is really our FAP program. Part of what we did last year was not just invest in our supply chain but also we augmented our pipeline in some key areas that we think are important for the future. FAP is clearly an interesting target. We think we have the absolute best pharmacophore in this space. We've got data in several hundred patients with lutetium and actinium and natrium. So we have a data set that we can really design late-stage trials around right now.

We're at the stage where we're getting the CMC package together so that we have a very clear run at late-stage studies with this asset. It is a theranostic pair. So we are developing the imaging agent as well. So really great opportunity and very much a pan-cancer indication. I think one of the challenges that we'll have over the next couple of years is both FAP and CAIX have applicability in a very wide range of cancers where we've seen clinical utility in a fairly wide range of cancers. We're going to have to be disciplined about how we prioritize some of those clinical indications. And that's some of the decision making that we're going to have to make over the next 12 months, particularly for this assay. It's a lot of different directions that this could go.

But however you rack and stack in 1 of the things that I think I want to get across to you today is just the opportunity that we have in the business. So not just on the precision medicine side of things. I mean we're butting up against $1 billion of revenue. We see a clear pathway to surpass that. So there's a large addressable market there for our products that we can continue to take but really also that future frontier of that therapeutics business. And when you look at across all the different disease area franchise that we work in, it's a very substantial opportunity for the company.

So without going into individual, and I might just leave this slide up as we go into Q&A but this is what we have to look forward to in 2026, I particularly want to call out the near-term readout on Part 1 for TLX591s, ProstACT Global and also the resubmission of Pixclara and Zircaix is proceeding as we expect but so many other milestones to be hit this year, both on the therapeutic side and the precision medi side.

But I -- and it's not just the slide, the way it's written, but it's really in terms of how we think of the key catalysts for this year, it starts to reflect Telix moving much more with that therapeutic focus in mind. That's the prioritization of our investment. It's where we think a lot of the news flow will come out of this year. So I think it's a very exciting year ahead and really builds on the bedrock that we created in 2025 for the company. So I'll pause there. And Chris, over to you.

Thanks, Chris. Feel free to raise your hand if you have any questions in the room. Perhaps I'll start. So perhaps at the top left of the slide there, Chris, the prostate therapeutic, I'll take imminent as weeks more likely than months?

Yes, exactly.

Okay. And maybe then in terms of the Part 2 sort of randomized enrollment, how quickly does that get up to speed? And I know you sort of still think this is going to be launching in the relatively near term?

Well, we've got -- it already is launched. So we've got approval for Part 2 and it's recruiting in 7 or 8 countries. I mean...

In the U.S., sorry.

Oh, in the U.S. yes, so that will be subject to what the FDA says but we've had no difficulties with non-U.S. regulators in terms of moving the study ahead. We view this as a discussion that has to take place and will hopefully result in U.S. patients being added to the study in fairly short order. But we've had no challenges in moving the study ahead with other sophisticated regulators. So I think it's really just about hitting that milestone.

Yes. Got it. Okay. Zircaix, so you mentioned the positive Type A meeting you had shortly before the end of the year. Now you had to address some CMC deficiencies, which were raised in the CRL. Were there any other observations that had to be addressed as well? Are you following up separately on that issue? And maybe just an update on the timing of the resubmission.

Yes. So the whole span of topics that came through from the CRL are really all around manufacturing and comparability between our clinical and our commercial scale material. When we run clinical trials with radiopharma, we aren't typically using large commercial scale practices because you're dealing with large amounts of radioactivity. Radiopharma is still very much a small batch production or a small-ish batch production continuous type of environment just because you have a decaying product. So we had a bit of extra work, and it's the first time that anyone's put a PET biologic in front of the FDA, and it was our first time and their first time, and I think we learned a little bit together.

There were some things that we were surprised at that we've had to go back and fix but they're not significantly adding to time lines or anything else like that. The -- we have an upcoming meeting with the FDA to look at the clinical comparability data that we have proposed or the clinical comparability strategy that we proposed when we filed the BLA that was deemed not to be necessary by the FDA that analytical comparability would be sufficient. But upon review of the package, they determine that they wanted to see clinical comparability. And so that's where we landed. Fortunately, we did a clinical comparability study, and we have an open study protocol that we anticipated, perhaps European regulators wanting.

So we're in pretty good shape in terms of that package. So once the FDA tells us that they're happy or otherwise, we're in a good position to move ahead with that refiling.

Thank you. Any questions from the room at all? Yes.

Thank you for the presentation. As we think about the next 5 to 10 years in terms of radiopharmaceuticals, what do you see as the biggest challenges for that market to really scale up both on the therapeutic side but also on the infrastructure, supply chain, et cetera.

Well, I think it is exactly that. I think it's the infrastructure and supply chain but I mean that is somewhat an investment-driven outcome. I mean, I think we see a lot of companies that are out with very novel radionuclide even things like actinium where there really isn't a commercial supply chain available. I'd say that lutetium has an established supply chain but it's vulnerable, and vulnerable supply -- I mean, even when you take something like technetium that we use 40 million times a year around the world, it's still a vulnerable supply chain. So -- these are definitely challenging. I think that execution lines, clinical execution wise, the biggest issue is the lack of clinical infrastructure to support this.

When I -- on the rare occasion that I lose sleep at night about this industry. It's a lack of text, it's the lack of practitioners. It's how do we get radiation oncology up to speed on these therapies, how do we make it easier for medical oncologists to integrate radioactive therapies into standard of care? How do we run clinical trials where we actually prioritize the integration of radioligand therapy with standard of care rather than the sort of traditional head-to-head approach that nuclear medicine favors.

So yes, how do we -- I guess the fundamental problem when we have to solve is how do we make this class of drugs available to a more general prescriber base? And that's a really tough challenge to solve. There's a lot of opportunities as well there for different types of organizations that will do things in a different way. Anybody else have a question or comment. Still got a few minutes left. So well, maybe you'll have to throw one at me.

Pixclara, Chris, if you don't mind. So you got the NDA resubmission there on the top of your slide. I believe you said I read it down, very shortly, will be the time line...

Well, we wanted to get it done before Christmas, but everything moves at the speed of cold molasses before Christmas. So it's very, very close to getting done. We're just kind of dotting the Is and crossing the Ts on that package. So yes.

But to clarify your expectation, both Pixclara and Zircaix you still expect to be commercial opportunities within the calendar year.

We do. Yes. And Pixclara, we have -- we believe a very clear agreement with the FDA on how to move forward. We have the data that we need to satisfy the more the data analysis that they need to be satisfied to move ahead. Unlike the -- it would be very tempting to -- when a company of our size, and we submitted 3 drugs last year, we got 1 over the line. We had 2 setbacks. It would be very tempting to ascribe a kind of systematic issue there, but there isn't, they're just completely different.

Pixclara was a single CRL topic around data analysis and what the FDA -- and by the way, at this stage of labeling. So we're not talking about mid-cycle review, we're talking about at the stage of labeling, right, where we had a disconnect on how the clinical data manifests itself in the submission.

That single topic issue has been we believe, result in our resubmission. We had no CMC issues. We had no manufacturing-related issues. That package is very straightforward from a regulatory perspective, from a CMC perspective. It's the exact opposite with Zircaix. Zircaix has a gold standard confirmatory Phase III, knocked all 14 primary and secondary end points out of the park. The issue is not clinical. The issue is really around manufacturing. It's a super complicated asset.

I dare say, we probably expect to see -- although I don't know that the agency has such an appetite for these days but we'll expect to see revised guidance industry come out of the experience that we had with the FDA because I think the first time that somebody really put a full package around a biologic-based radiopharmaceutical in front of them. And when you have a reviewer that's looking at your product as though it's a cytotoxic ADC, you're going to have some disconnects in terms of kind of understanding.

So I think it's -- we certainly feel like we came out of the process with our 2 setbacks last year, a stronger company. We understand what we're going to have to do differently in the future. We have a much more paranoid lens around how radiopharma is different and not different relative to other sort of biologics. And I think that's a competitive advantage for us to really understand where those issues are with the agency. So the challenge you have when you're submitting drug approvals, is that's the end of the road, and that's where the success happens or it doesn't.

Before I let you go, I do want to ask you 1 on Alpha. But before I get to that, we still have a couple of minutes. So just additional opportunities, maybe taking a step back on your existing commercial product. So you mentioned late last year, you had some good Phase III data from the study you'd run in China, with Illuccix. You said today that's now been filed. Maybe just contextualize that opportunity for us? And also Part B of the same question, the BiPASS process. I mean moving upstream, you talked about the challenges involved. How near term and how realistic are those opportunities?

I think they're very realistic. And we see more and more clinical interest in using imaging at the front end of the decision-making process. And -- but no 1 has really collected the data and made the clinical case yet for doing -- so that's why the buy. There have been small academic studies that have done that have shown some promise. We've learned from those studies, and we've built on them. I think our clinical team does a great job of monitoring the state of the art.

The BiPASS study is a really well-designed study that's going to be a label generating study because we've agreed with the agency that it's a label generating study. And I think that it enables us to really move upstream from where we are today and impact patients much earlier in the journey. The TAM associated with that is massive. If we can reduce the number of biopsies down to 200,000, 300,000 biopsies a year, we can more or less double the market opportunity for prostate cancer imaging but it's done in such a way that it's really additive to health care.

I mean if you look at the cost, both in terms of the economics of clinical service provision and the morbidity and impact on the patient that moving upstream is really impactful. It's a no-brainer from an economics perspective. So I think that's a very bright spot for the company in terms of driving value. I think that when you look at Telix as a company, commercial execution is something that we do really well. That should give you confidence that once we have, for example, Zircaix approved, we'll go back into that same referral physician that we've built a very deep relationship with it's going to be a rapid product adoption. I mean the -- my greatest personal disappointment last year was not getting Zircaix [ over liked ] because prescribers are waiting for it. We actually kept our expanded access programs open for Zircaix and Pixclara, just continued to show our commitment to patients. We did that a pretty significant cost company.

So we're keeping that enthusiasm alive, but really want to see those 2 products out of the market. Regarding China and Japan. China is a strategic opportunity that's really about paving the way for therapy. That's the key interest that we have in China as well as our partner interest. Japan is rather different. Japan is probably the second largest homogenous market for nuclear medicine products. It's got an advanced PET procedure code that's reimbursed at a decent level, not too far behind in the U.S. We see about 110,000, 120,000 scan market opportunity in Japan at a good price point, that's well and truly worth prosecuting -- it's probably the best opportunity that we have in Asia.

I promised a question on Alpha, if you don't mind, Chris. I'm going to rush you though. So maybe just 45 seconds on what you think with alpha-emitting therapies.

I think it's got great promise. It's just that we probably don't develop them yet in the way that we should. And I think that there's a long way to go on the supply chain before they're viable, but we and others, of course, are working on those.

Great. Thank you very much for your time. I appreciate it.

Great. Well, thank you, everyone, for joining our fireside chat with Telix. My name is David Dai. I'm one of the biotech analysts here at UBS. [Operator Instructions]

In the meantime, I'd love to introduce Kevin Richardson here, the CEO of Precision Medicine of Telix. It's a great pleasure to have you, Kevin.

Yes. Great to be here. Thanks for inviting us.

Excellent. Great. So Kevin, starting just can you provide a quick high-level overview of Telix, including both your diagnostics and also therapeutic platforms?

Sure. Yes, excited to. As you know, we're really one of the few pure-play radiopharmaceutical companies that really focus on 2 platforms that work really well together, the diagnostic platform, which we've initially launched Illuccix and now Gozellix into and, of course, have several others in the diagnostic space. We platform that technology with a corresponding or pair -- a therapeutic pair on the therapeutic side with our 591 therapy, 101 and 250 therapy. And then one of the unique differences around Telix and the rest of our colleagues out there is really around our TMF solutions as well, which really brings together our ability to supply -- we call it our strategy is from the isotope to scanner or isotope to injection room so that we can supply that all the way through the supply chain system.

We've done -- we've demonstrated that really around some of our most recent acquisitions around ITG, some real brain power and property down in Houston as well as Optimal Tracers in California; Seneffe in Brussels, Belgium. And then one of our latest ones is RLS that really brings together really the power of really regional manufacturing all the way through last-mile delivery to our customer base. So really making sure that we own all parts of that is important to the overall strategy of Telix that we've been laying out over the last couple of years. And then you've been able to kind of see that as we've made these acquisitions to really manage that strategy to really be a one-stop shop from isotope all the way to the injection room.

What about your therapeutic business there? Can you tell a little bit more about that?

Sure. The therapeutic business is really anchored right now around our 591 therapy and our antibody approach. As you know, we've finished our Part 1. We're waiting to move into Part 2. We haven't given really an update on when we're going to give that news yet. But in -- outside the U.S., we've moved into recruiting Part 2. So really excited around our 591 therapy. And then the 250 therapy around clear cell renal cell carcinoma and 101 is really moving forward well, and we have updates on that as of the last quarterly results.

So it's a big part of the way that we look at the market is that we are not a diagnostic company. We are a therapeutic company that is really leading the way with our diagnostic business. There's a couple of ways that that's really important is that the diagnostic business is really building key relationships with payers around the world. It's building key relationships with regulatory bodies around the world. And most importantly, it's building relationships that we believe we'll be able to capitalize on in the customer base.

So we're in thousands of accounts around the U.S., and it's really important that we build that nuclear med, that urology and ultimately, that medical oncology relationship so that when we develop and launch and go to market and start to commercialize the therapeutic, we have that relationship in hand. And we'll have multiple diagnostics along the way with that. So we'll have great payer relationships as we go into that process as we -- even now with Gozellix, we're diving deeper into some of the commercial payers as we continue to build this database relationship with payers.

Got it. That's really helpful overview. So let's focus on the prostate cancer diagnostic business, which is the precision medicine and your lead program, the commercial program is Illuccix. And over -- in the last quarter sales, we saw sort of like flat $155 million versus $154 million in the second quarter, but we did see volume growth grew about 3% quarter-over-quarter. Can you just maybe share us -- share with us some of the dynamics you're seeing? And what are you seeing in terms of the ramp and adoption of Illuccix despite TPT pass-through expiration?

Sure. So we were really extremely pleased with Q3 2025. As you know, Illuccix lost pass-through in the start of the third quarter. So it was a pretty even playing field for a little bit. I'd say even in the status of now, quite uneven when you know that by that time, Gozellix had been approved, HCPCS code had been established, and then we were just waiting on a transitional pass-through approval from CMS. So we were quite pleased with Q3 results, understanding all those dynamics at play. And we're quite pragmatic about our approach to commercialization. So as things evolve in the strategy, like we had planned for this event, we had planned for transitional pass-through, but the tactical execution of that kind of has to wait until those milestones are realized.

So as we think about Illuccix kind of managing through Q3 and our sales and marketing team's ability to not only hold on to that business but grow it on a unit basis was really important. So really managing a simply put strategy of going deep into accounts that we have already established with Illuccix. So either getting more patients into those accounts that use us mostly exclusively as well as going deep into the market share split accounts where they might use two different PSMA agents up to and including more of a wide strategy, how do we bring on new scanners that are coming in and/or competitive accounts.

So managing that in a very dynamic marketplace takes a real dogmatic approach and disciplined approach to the way we commercialize. And so I would kind of relate that to the modular approach that our customer service or customer-facing team really approaches. We center everything around that relationship at the Territory Manager level. And then we surround that territory manager with subject matter experts to help facilitate the conversion or the deep strategy from a market development team that really focuses on going deep into accounts and really working with the local referrers to drive more patients into that, educating referrers on the power of PSMA Illuccix.

And believe it or not, there's still a lot of value in that, while PSMA has experienced a massive growth streak over the past 3 years, we still get urologists that refer for bone scans that we have to reeducate. I personally have experienced that with friends around from California to Phoenix to New Jersey, where they are looking for a place to get a PSMA scan because the urologists didn't refer that. So we have work to do in that, and that's that last little 10%, 20% of the penetration of the TAM that we're looking for is the way it's defined today. And then when you really think about the market development going deep, then we've got the -- once we get an account converted, they need to make sure that the scanners are set up right.

So we have a medical imaging specialist that comes in and makes sure the scanner is ready for a gallium scan and the customers know how to read and the differences between the two. We believe that Gallium has higher inter-reader agreement, better clinical accuracy. And to do that, we want to make sure the scanner set up for that promise to be fulfilled. And then if -- once you switch to a new product, it's a little bit different of a process. So we want to make sure that our reimbursement specialists are there, our field market access people to make sure that the paperwork is done correctly and everything is smooth with the reimbursement.

And then finally, if you really want to understand at a deeper level around the clinical science of inter-reader agreement and indeterminate bone lesions and how to really differentiate the two products in that conversion, then a big part of that is our medical team, our medical affairs, medical science liaisons. They're subject matter experts specifically on the difference between gallium and F-18, of course. And they play a big part of being able to help peer-to-peer differentiate the two products.

So it's a real customer-centric customer-facing approach that we call it, it's a modular approach that requires a disciplined approach from the TAM and then to manage all that value in the Telix future pipeline as we educate customers on that to manage that value so that price really isn't the reason that they choose Telix or not. It's the value proposition that Telix brings as a company and as an individual function that's solving some of their problems.

Got it. Got it. It's exciting to hear that not just price, but also many different factors at play, right, that really helps drive growth of Illuccix in many different markets. Now excitingly, with respect to the new drug that just recently got approved, Gozellix, right? And those TPT pass-through. And what we saw in the third quarter was that you actually increased the guidance, right, from $770 million to $800 million to $820 million, right, top line side of things. So this means that you're seeing some numbers from Gozellix launch perspective. So just help us understand, Kevin, what are some of the things you're seeing on the momentum of this Gozellix launch so far heading into the fourth quarter, especially after the TPT approval.

Yes. Sure. Well, we started the Gozellix story 3 years ago. And so there's a lot of things that have changed in the past 3 years in terms of reimbursement and the market and why we wanted to bring Gozellix in. So Gozellix is a true innovative product. We brought it in as a part of life cycle management, really focused on being able to reach not only urban and suburban areas, but more rural areas. So the focus on Gozellix development and the true innovation was around the stability of shelf life. How long can we keep the isotope on the molecule and get it to where we want it to go so that you don't have indeterminate bone lesions, you don't have separations. And so it was a big part of the strategy.

But part of what that enabled us 3 years ago as we started was to understand then if something came off transitional pass-through, it went straight into a bundled package, right? So we knew that we needed to truly innovate in order to ensure a HCPCS code. And so it wasn't really about a matter of expanding production capacity or anything like that on a cyclotron. That's more about -- it's not about the efficacies reached and the economies reached and increasing the capacity size. It's about how far we can go with the product to really reach the full potential of the TAM.

So we started that 3 years ago. And as we edge towards that, CMS changed a bit, right? They came out with MAC pricing. And so we were able to manage then our strategy and tactics based on what the scenario would be at launch if it were under MAC pricing and assuming that we did or didn't get reimbursement pass-through. So once we got a HCPCS code, well, then transitional pass-through was just a little bit closer. So we were able to tighten up our tactical plan on how we were going to execute that. And so all of that was a part of a very disciplined approach that started 3 years ago as we honed in on what would be October 1, 2025.

Now with all the splashiness going on at one end of the market, if you will, around pricing and kind of the F-18 battles, we tried to keep our eyes on the prize, if you will, which was maintain a dogmatic approach to pricing and a dogmatic approach to the execution of both our deep and wide strategy, where we were going to go get more patients, where we were going to take share and where we're going to open up completely new accounts. And that was an important part of that as we got closer.

So now we got HCPCS sometime in early September. We were notified about CMS in late September, really a week before. So in the world today in hospitals, as you know, there's just some issues around pricing committees and things like that. So we're incredibly excited about the progress we're making. We're excited about our Q3 results. So once we saw our Q3 results in the midst of all that splashiness, we were able to raise guidance and what we thought was appropriate for our progression and our progressive move from Illuccix and Illuccix split accounts to what would look like to be more Gozellix-only accounts kind of moving forward.

Remember, HOPS accounts are a real target for that and -- because of their CMS reimbursement, but they too have different payers inside of a single HOPS. It's not just CMS. So really managing that mix has been an important part of that progressive planning process. The more data that CMS gives us that's more accurate and actual, then we can quit speculating and start driving through the scenario plan that we built for that. And that's really where we are right now today.

So we're in the middle of that tactical execution, and we feel very comfortable with the progress we've made and excited enough about that progress to raise guidance. And then, of course, we haven't given guidance for 2026 yet. But as we see progress in, you'll see that in the first quarter, and we'll be happy, and we've been pretty accurate with our guidance so far. So happy to talk more about that in the first quarter.

Absolutely. Looking forward to that. Just -- anything you can share on the -- after TPT was approved October 1 so far, it's November, anything you can share around how the launch for Gozellix looks like so far? Any kind of physician feedback you're hearing from physicians on clinical and logistics aspects of Gozellix?

Yes, sure. No, like I said, it's progressing according to plan, and we feel comfortable with that. Again, there are pricing and new product review committees that we are in big accounts, which these are HOPS accounts that we have to kind of manage through. But the feedback of the first cases that we've done are great, fantastic deliverability of the product through our radiopharm partners and our own radiopharm RLS has been a significant improvement in terms of just their ability to manage multiple doses and manage the operations inside.

We are continuing to work on what we call our distant pet strategy. Those accounts are a lot -- a little more slower to come to market because of their sensitivity to reimbursement. They're smaller hospitals or more rural. So we're working through those issues as we start reaching further and start reaching the promise of Gozellix outside. So the promise of Gozellix in urban and suburban areas is flexibility, reliability and delivery, more timeliness of dosing and you're not as worried about -- you can get a dose there earlier in more metropolitan areas because you can deliver more gallium quickly. And then in the more rural areas, we can just go further, and we'll continue to start driving into that.

So I think from a progression standpoint, there's been a lot of work done previously, and now we're just tactically executing that through our sales and customer-focusing team. So very happy.

Got it. Got it. And you mentioned about that 10% to 15% of potential market that Gozellix could potentially enter. How has that been so far?

Well, I think it's progressing as well. Like I said, that's more of a price -- it's not a price-sensitive market. It's a reimbursement-sensitive market because they are so small that this is a big expenditure as a percentage of what they do. So we're working through those details now on their pricing committees, and they were waiting for transitional pass-through. So that's progressing.

As we look into Q1 and beyond, we will give guidance based on PSMA and not really the split between Gozellix and Illuccix, but we are very positive about how the progress of the uptake has been and the physician feedback has been great in terms of the deliverability and really the image itself has been very well accepted and adopted.

Got it. Great. And then moving on, you have this Phase III trial called BiPASS, which is going to -- going after patients with prostate cancer diagnosis. Can you talk a little more about this trial? And how do you think you're able to use this trial to expand the market logistics for that?

Sure. Yes, we were excited about BiPASS. And me as a man, I am very excited about BiPASS because of what the alternative really is, right? -- that the alternative right now is a pretty invasive procedure with a probe that is anchored in the anus and then a template biopsy is delivered 12 to 40x. So it's quite invasive for what that looks like. And I would say that PSMA can improve on the sensitivity and specificity of that as well as the adoption. There's 800,000 to 1 million biopsies a year in the U.S. and about 20% of men say no. They say no because of how invasive the biopsy is and some of the side effects of that biopsy.

So the number of biopsy itself in PI-RADS 1 through 4 is that kind of adoptable market piece that we're looking at around that 800,000. So if you look at an existing TAM that's mostly BCR at this point of about 600,000 plus then you can see it more than doubles that available market to us and really changes where PSMA sits in the patient journey. So instead of taking it from a staging or a biochemical reoccurrence after definitive therapy, it puts you prior to definitive therapy. So we start looking at gallium scans in terms of serial play, right? You get it at the diagnosis, you get it after the definitive therapy for maybe a response to the therapy and what that may look like kind of along the way can give us multiple times that they'll want to use a gallium scan.

So we see it as an amazing patient benefit and more than doubling of the market in a step change with a positive trial. And then we see that we can continue the BiPASS trial and really move into the other section of PI-RADS 5 and really kind of paint that whole picture with the PSMA scan. So the way we position it is that it gives the patient the one and done or none and done just based on how positive or negative they are on the scan. So either one biopsy just will be more precision. It would be right where the tumor is, and you don't have to do a template to figure out where it is because you know right where it is up to they get a clean PSMA scan with high predictive value. So they're good to go.

And as you know, there's a lot of anxiety around getting that PI-RADS scan and really understanding where you're going to get a Gleason score because those two together give you really a risk stratification of metastatic disease, how aggressive is this and/or is it metastatic. And so the ability with BiPASS upfront to alleviate some of that and give them clinical decision-making power early in the process is going to be really important.

Got it. That's really helpful. And so on that front, anything you can say in terms of data expectations or when should we be expecting completion of the trial? When do we actually think we actually see any data coming out of it?

Sure. No, it's an interesting question, and we're all kind of curious about that, but we haven't disclosed anything on that yet. We have disclosed that we've done our first patients in Australia. We're finalizing everything with the FDA now. We've got sites registered and lined up. They're just about to start recruiting, and we'll announce that as soon as we get that first patient in the U.S. Remember, the follow-up on a diagnostic trial is not like it is on a therapeutic trial. So we're seeing pretty quick recruitment in Australia. I mean if you -- imagine, if you will, you've got a patient, it's really an intent to treat -- it's an intent to biopsy trial. Meaning that if you see clinical indication in a patient that you want to biopsy of them, then they qualify for BiPASS biopsy.

It's typically a rising or a high PSA and a PI-RADS 1 through 4, and then they would be indicated for a biopsy. So they're simply just adding on a PSMA scan, which will give them more information. So we see it as a pretty fast recruiting trial. I mean, still to be seen, but we're seeing good uptick in the trial in Australia right now as we kicked it off. So we -- hopefully, we'll be able to give some more guidance in Q1 once we get the U.S. space going as well.

Got it. That's helpful. Great. And moving on to your other diagnostic programs, Pixclara and Zircaix, maybe focus on Zircaix, so far. Now we've recently seen that the program is actually recently being included in a number of guidelines, including SNMMI-I, EANM, ACNM. So could you talk about the importance of the inclusion of Zircaix in those guidelines?

Yes. I think that is a really important step in the society backing the product. That comes from 3 years of confidence in Telix and our PSMA agent and our ability really working with those physicians on PSMA to understand the value of that scan that translates easily over to a ZIRCON study that came out that has really high sensitivity specificity as well. So that confidence is really a platform confidence now in that PSMA PET drug where they want to see this enacted. It also comes from an expanded access program that we did in many sites around the U.S. as we came off the trial, we went to expanded access. So there were a lot of patients that benefited from that trial that really adds to the value of what the society wants to do with that.

Remember, it's that same scan anxiety comment that I said before. You typically get a kidney lesion identified on some kind of other scan that you came in for. And they said, here's what's going on with why we scanned you. However, we see something in the kidney that we were going to need to investigate and/or the horrible words of watch and wait, right, that we're just going to have to measure the significance of this lesion by the size over time. Is it growing fast or not? And as you know, ccRCC, clear cell renal cell carcinoma, is one of the most aggressive forms, right? So waiting 6 months or a year between scans may not be the best time line for that patient.

So being able to see those smaller lesions and get them identified quickly so you can get the appropriate treatment as fast as reasonable is a more appropriate treatment algorithm for that patient. So that's why Society of Nuclear Medicine and the same for the European society put that in the guidelines as a proposal that they really see the value and what that's going to do for their patients.

Now that also leads the way to another important guideline, which is the NCCN guidelines, which will happen as soon as we get the product approval. We feel pretty confident that the NCCN is favorable. The other societies are favorable, and that's an important step as we get to reimbursement and how the insurance companies will reimburse is based off that NCCN guideline. But the confidence of the nuclear medicine societies that have really been the ones working with this product is really important in terms of getting to that next step. So it would seem as though we have their full backing on moving forward with that product, which we know we have because we talked to them in alliance.

That's great. Yes, on that front, anything you can update us on in terms of the submission progress so far? Any kind of remediation process with the third-party manufacturing facility? Anything you can share on that?

Sure. Yes. Well, I mean, it's still working towards that Type A meeting and submission dates for that. So we'll let you know as soon as we get that and move forward with that. As far as what we're doing on the CRL, we know that we have a clinically acceptable and safe product. The ZIRCON study demonstrated that. But like all true innovators, we're going for a BLA with radiopharmaceuticals, which is kind of a first-in-class and so we had -- we were working through that educational process on both sides to get the manufacturing where and how we want it for the scale-up and production of Zircaix when we go to launch that around the U.S.

So more to come on that as soon as we make that public and move forward with that. But the team is working tirelessly for that Type A meeting, which means that we can then submit post that. So really excited about it.

Got it. And then for Pixclara resubmission, you've guided to resubmission by the end of the year. What are some of the key gating steps for you to resubmit the application again?

Well, we had the Type A meeting. So the biggest step was really getting in step with the FDA and what they wanted to see. This is a 505(b)(2), which means that it's using the existing data, and we've come to an agreement with the FDA on what other data they want to see or what data and how they want to see the data. So we are just working towards that, and we're holding tight to our submission in 2025. So again, once we make that, then we'll -- they have 60 days or so to respond. And then we'll -- that's when we'll be able to announce when we get that back from them of when the next PDUFA date might be, given that they accept the file.

Got it. That's helpful. Any changes in terms of the FDA interactions given all the changes that's going on with the FDA?

Well, I mean, I think that's a question for really all of us in the industry today is how that's managing. So Telix won't be held to any other standard than anyone else. They won't get less interaction than anyone else. So it will be an industry issue moving forward. But we continue to have great conversations with them. We continue to have the appropriate level of interaction with them. And so far, we're pleased with the progress we're making on both those fronts and don't feel as though that there's -- we've been negatively affected more than anyone else in the industry by just what's going on in general with the FDA and then what's happened in the last 38 days, I guess it is, right? Hopefully, there's some news today that may break that, but...

I hope for that. And the last question on Zircaix. How confident are you that you won't need a clinical trial for the resubmission for that?

Well, we're comfortable with where the FDA communicated with us what we needed to do and what we needed to demonstrate in terms of getting it to a commercial stage product. Again, the clinical trial of ZIRCON was a well-constructed trial and had great results. And so it's not that it's not an approvable drug. We've just got to manage it through that process. And again, innovating is difficult sometimes and being a BLA radiopharmaceutical first-in-class is always just leading the way and coming to an understanding across some of those issues that may be a little muddled in some areas. But we're pretty clear on our direction. The team has clear direction and good communication with the FDA, and we just continue to work those things out as we move forward.

The commercialization of Zircaix is really kind of exciting because our TLX250, when it crosses over and gets approved into Zircaix, it would be inside the same commercial strategy, right? So it's still a urology call point. It's still a urology referral into a nuclear medicine like reading room. And so we're prepared as a commercial team to take the synergies of that and bring it to bear in the marketplace. So like I said, the same thing that holds between diagnostic and therapeutic advantages of having a diagnostic team. It also has the same advantages of having a previous diagnostic, right? We have great relationships with payers, great relationships with regulatory bodies and great relationships with customers. So we have a landing place for a product that we have an existing sales force that's out there each and every day calling on them.

So we're really comfortable with the go-to-market plan. We've done a lot of unbranded like education around clear cell renal cell carcinoma in the urology marketplace and the way that they're managing it today. So we're excited and look forward to the day that we do get that approval and kind of enable that selling organization that put it bluntly, has done a fantastic job in the PSMA market and be able to utilize that same approach, that modular customer-facing approach to be able to use it with two products. I mean, it can only make them stronger, right? It can only make us more valuable in the marketplace in terms of our customer interaction and just a much simpler sell as you start thinking about the urologist and how they are referring into these diseases that were diagnosed one way 2 years ago, you see the same thing that's going to -- we believe will happen inside of ccRCC.

Got it. Great. Excellent. So we've got about 3 minutes left. I love just to kind of switch gears and talk a little bit more about the therapeutic business, especially focusing on TLX591, especially with the ProstACT global trial Part 1 data readout, what can you say about like what's the top line data expectation, we should be watch for safety, dosimetry? What sort of safety of this dosimetry data we should be looking for here?

Sure. Well, I think that as we've disclosed that we're through recruiting for Part 1, and we've moved on to Part 2 basically outside the U.S. Inside the U.S., we're waiting for the data readout, which we haven't disclosed yet when that's going to be. It's still percolating, if you will. So we're incredibly motivated to kind of move through that, as you can expect. And I think that with any therapeutic trial, you're just wanting to make sure that you're at the acceptable levels of toxicities and you're showing probable efficacy in terms of what we're looking for. So it's just a Part 1 to really move into Part 2. And we think it's a great way to really demonstrate the value of the product in a way of moving into that really Phase III clinical trial.

Yes. Well, I guess the question is what level of safety that will get you confident to move into a Phase II -- Part 2 study?

Yes. We really haven't disclosed the levels that we're looking for yet. So we'll have more to come on that.

Got you. Makes sense. Okay. Great. And then just lastly, any kind of near-term milestones you want to highlight over the next 6 to 12 months that we should watch for?

Well, I think -- well, for the therapeutic business, it's exactly what we're talking about, right? So we've got to initiate Part 2, give the readout and then move to that interim data readout of Part 2. So that's a big therapeutic milestone. I think from a -- it will be a big milestone. We'll be talking about our 2025 results in Q1. That will be a good indication of the success that we're seeing in Gozellix and that continued move when you see our guidance for that, that will be a big milestone in terms of our ability to execute in that PSMA market, given all the dynamics in that market.

And then really, the launch of BiPASS is the game-changing kind of step change in terms of launching it and then the recruitment period and then ultimately, what that looks like in terms of getting to that positive, whether that's -- when we can really give that expected date will be a big time over the next 1 to 3 years will be a big change. And we think that, that really moves the game, like I said, from this really battle between serial scanning of patients and puts us right upfront in the priority position and really establishes ourselves as the market leader, we think, in prostate imaging.

Okay. Great. Well, with that, we're out of time. Thank you, Kevin, for joining us. It's a great pleasure to have a fireside chat with you.

Yes. Thank you. Thank you for your time. Thank you for the invite.

Thank you so much. Yes. Thank you, everyone.

Welcome to our next fireside chat. I'm Robert Burns, Managing Director and Senior Biotech Analyst, H.C. Wainwright. And I am joined today by Christian Behrenbruch, the CEO of Telix Pharmaceuticals. Christian, thank you for joining us today.

Yes. Thanks for the opportunity.

So one of the things that I first wanted to start off with was obviously, Telix has experienced rapid growth and transformation over the years. So can you share some of the key factors that have contributed to the success?

Well, I think the company is just really passionate about radiopharmaceuticals. I think one of the unique aspects about the company is we don't really believe in isotope platforms, right? We think that when you develop a radiopharmaceutical, you should look at the clinical application that you want to solve.

You should think about what pharmacophore achieves your biological objectives best. And then you should choose the right isotope for the job. And so one of the things that I think is really special about the company, and it's reflected in the infrastructure that we've built over the last -- almost -- company is almost 10 years old, 8 years as a public company is that agnosticism.

We want a -- we're very -- we're a pure-play radio pharma company. We believe that precision medicine is really important. That's kind of something that isn't particularly endorsed. It's not a pharma kind of concept. As a concept, we get compared -- as a consequence, we get compared a lot to other companies like Lantheus, where we're not a medical imaging company. We're a therapeutics company that does precision medicine.

Yes. You sort of fit in this sort of dual space because either you're like Marietta Oncology, where it's purely therapeutics or Actis, which is purely therapeutics or medical imaging. But you're actually neither -- you're a blend between the 2. And I think that, that's what's contributed to your success.

That's right. Well, in the business model was notwithstanding the odd CRL and the odd speed bump in our development programs. I mean, this year was an ambitious year, 3 drug approvals planned. But the regulatory and go-to-market pathway for the imaging products is relatively straightforward. And so -- I mean, at least conceptually.

And so as a consequence, we had the opportunity with Illuccix and Gozellix, which we got approval for earlier in the year to generate meaningful revenue streams to self-finance our therapeutics. And so we don't just think that it's important for patients.

We think it's an important -- like it's a business concept. And the one thing I'll point out with radiopharma, like I have to tell you, I do not understand radiopharma companies that just do therapeutics. Like the one defining aspect of a radiopharmaceutical is that it emits radiation, you can detect it.

So you can take your drug and you can put it into the body and you can see everywhere from your toes to your nose where the drug goes. And why wouldn't you use that information to the full benefit of patients, right? So for every target that we develop, we develop an imaging agent and a therapeutic, and we think that, that's commercially and clinically the right thing to do.

Yes. Obviously, there's been -- you have a significant revenue stream from your PSMA imaging agents. Talk to us a little bit about how you plan to potentially expand the market size for Illuccix and Gozellix?

Yes. And so we were second to market behind Lantheus. We actually filed our NDA a month before Lantheus did. But because our product is a lyophilized vial, it's not a radioactive fill-finished product. It's a different part of the FDA that inspects. And in fact, during COVID, we wouldn't have gotten an inspection at all of our manufacturing site if they weren't a vaccine site also. So it was like kind of -- we were even just lucky to get an inspection.

So we ended up coming out late. We had a PDUFA delay of a quarter, waiting for a site inspection and then we missed the CMS entry window for pass-through. So we ended up coming to market second, but we've been really focused on, all right, how do we how do we really command our market share?

So the first thing that we did was there isn't a single market for PSMA imaging. It's a highly segmented market. Lantheus mostly chose to focus on the academic centers. It was a large volume, kind of low-hanging fruit, receptive user.

When we came out, our product is a nuclear pharmacy produced product. So it's got a much more distributed manufacturing infrastructure and that was better aligned with the IDTF market, private radiology, private imaging center market. So we went for that, and that's how we got our foothold. And so we have, in some regards, a somewhat complementary customer base, and there's overlap, obviously.

But -- and so when we look at market expansion, it's really about building on that segmental analysis. And there's 3 ways that we're doing that. The first is we have just gotten the HCPCS code. We're expecting pass-through shortly for Gozellix, which is a second-generation product. It's much more similar in some respects to an F-18-based product, which is a -- you can make large quantities in a single delivery of product, academic centers like that. They don't like continuous deliveries during the day.

I'd like to know that their chunk of material is sitting there waiting to use and we can do that with Gozellix. And so that gives us an opportunity to really offer something compelling to the large HOPS accounts. Obviously, having a new reimbursed product will be helpful to that as well. So there's a market access strategy that's kind of overlaid on that.

The second way that we're going to expand market is Gozellix has a long shelf life, long stability when it's produced out of a nuclear pharmacy, which means that we can transport a dose further. We think there's about 400 Pet scanners in the U.S. that have never tasted PSMA. It's about 15% of patients. So there's a bit of white space there to pick up that in the past, the trains, planes and automobiles to get there have sort of got there.

And then the third is we've just announced that we started a Phase III trial called the bypass study. This is a -- this is not intended to replace biopsy, but it's supposed to direct biopsy towards the most beneficial patients. And I think we all know there's well over 1 million biopsies are done in the U.S. every year, and 80% of them are not of value to the patient.

And so we think that if we can use imaging to triage that process, that can add another 750,000, 800,000 scans to the TAM. It is a market doubling event.

How difficult do you think it will be to change that standard of care that leads the patient down this therapeutic path? Like how much of an unmet need is there? Because I remember during your Investor Day that one physician with that tool, it doesn't sound very nice. But how hard do you think it will be to change that treatment path?

There's already academic center starting to think about it. If you look at the practice guidelines around high-risk men being imaged with PSMA already, there's already quite a bit of elasticity in the definition of high risk. So when we take a patient and we look at their radiological profile from MRI, it's really starting to become clear. If you can overlay PET on top of that, you can have a cascading triage. You can either say this patient has a PET scan and they're done. There's nothing to see or they have a PET scan, so one and done or one and you have a focal biopsy where you're minimizing the number of insertions of a needle. And you're really sampling the tissue where you should be optimally sampling the tissue.

And then the third sort of cascade is, yes, this is a patient that needs a template biopsy based on the combination, and that should be the minority of patients. So it was a long journey, frankly, with the FDA to get that protocol in place. It took us about a year of backwards and forwards because the truth is like people want tissue and tissue is important, and histology is the ground truth. But I think that for a significant majority of men, we can avoid the discomfort and morbidity and cost. And I mean biopsy is a relatively expensive and invasive process.

Yes. When we think about your imaging portfolio more broadly, obviously, you have Zircaix as well you did receive a CRL. But you recently announced literallt yesterday, I believe, that you have the plan for resubmission. So talk to investors a little bit about this because obviously, it was something that none of us were expecting. But now it seems like you have a path forward.

Yes, we've been really unlucky, and I really do believe it's kind of not luck. I mean luck is -- you sort of make your own luck, but it's -- these products are also incredibly novel. And that proposed -- that has some regulatory challenges. So we got a CRL for Pixclara based on a disagreement around clinical data. We thought we had buttoned that up in the pre-NDA submission with the FDA. But I really feel like that some realignment was required from the review process.

I think we have that realignment right now. We've had the Type A meeting. We have plenty of data. We're not going to have to run another clinical trial. So we see within the time frame of the year-end that we should be able to resubmit that data and satisfy the FDA. So Pixclara was a pure clinical statistical analysis issue, not a CMC issue, the CMC package for that product is very robust.

[ Zix ] was the exact opposite. We did a confirmatory pivotal Phase III trial. We have no clinical issues from the BLA review process. The issue is mostly around comparability between clinical grade, clinical scale material and commercial scale material. Again, we've obviously received a lot of unhappy feedback about that, but we, of course, consulted with the agency prior to submission. We thought we had agreed on analytical comparability as the basis for approval. And it turned out really in the review process.

I think that I think that the product was reviewed a lot more like an antibody drug conjugate than it was the PET tracer. And so we've got a bit of extra work to do. Again, I think the data that is required to satisfy the agency is data we have. We have a briefing package being prepared now that will go in, in a couple of weeks' time. But I think Zircaix really tripped us on the novelty. It's the first time a pet biologic has ever been put out there. And I felt like we were both reviewing it at the same time.

And it seems like the resubmission you plan to complete that resubmission in the fourth quarter of this year, correct?

That we're aiming to. We do have 2 483s on manufacturing sites that need to be -- these are not product 483s, they're sites 483s. And they do need to be remediated. So that's the main, I think, rate-limiting step, but we're obviously working towards getting that.

I mean we -- like our shareholders, we want to see the revenue streams materialize as quickly as we can.

Yes. Now that we've spent a good amount of time on the imaging portfolio, let's move over to the therapeutic side.

I'd appreciate it.

Not a problem. Obviously, you have a very robust therapeutic pipeline. So maybe provide -- first, just to frame everything for investors, what does that therapeutic portfolio include? because there's quite a bit of stuff under the hood there?

Yes, there is. We have sort of 3 concentration areas. So we have a strong focus in urologic oncology, and that really mirrors our imaging activities. So we ultimately aspire to have a portfolio in prostate, renal and bladder cancer, bladder, potentially being met by both CA9 and FAP as the relevant targets.

Prostate programs in Phase III, we just finished the bridging or the run-in study for the 591 program. Part 2, which is the randomized part of that has now started ex U.S., and we've got approval in, I don't know, like 7 or 8 countries to move patients into that study. So that's recruiting. And it will -- the Part 1 is really heavy on dosimetry and it's like very demanding on patients. So the recruitment was quite slow.

But the randomized piece should move along very quickly, I think, now. So that's the urologic piece then we've got a neuro-oncology franchise. The glioblastoma IPEX BRIGHT study is just getting started. It's a pivotal trial in recurrent GBM. And we've gotten nice data. We've shown disease stabilization, antitumor effect we believe, based on single-arm data prolongation of life. In that patient population, of course, we have to do more work.

That's what the purpose of that study is. So that really represents our second asset going into late-stage clinical development. Again, Pixclara is the companion imaging agent to that. So it hits the same LA1 target. And we use Pixclara very much as an integrated tool in the patient selection for that study. And then the third area is kind of a broadly kind of a musculoskeletal, it's stuff around sarcoma.

We've got a couple of opportunities in sarcoma, which is an incredibly heterogeneous disease, where you really do need to use a precision medicine approach. You need to make sure that you're selecting patients for your therapy. There's a lot of subtypes but it's a really interesting opportunity. So we have an antibody asset that we in-licensed from Lilly in that portfolio as well as, again, potentially FAP, where we think we have the best FAP hands down. There's a lot of FAP out there. We have the best FAP.

Okay. I look forward to your FAP. So focusing on your lead agent TLX591, it's a PSMA-targeted agent that incorporates 177-lutetium. When we think about that landscape more broadly, obviously, there are a few different assets that are in play there that are already FDA approved. And then we obviously, we have a few next-generation assets.

So give us a little -- I want to get your taste as to where you see differentiation for 591. And then let's talk a little bit about your next-generation PSMA agent as well because I think that, that -- obviously, there's been a focus on differences in radionuclide. So we'll get there after.

Well, so 591 -- the way that -- so there's only one approved agent, which is obviously Novartis' product. This is -- we're very lucky as a medical community to have this first product for it to have been successful and to really pave the way for the field. We all -- everyone in the nuclear medicine community stands on the sideline and cheers for Novartis, right? Because it's a tough sell, right, going out and selling radioactive drugs to oncologists is a tough sell.

And if you look historically at nuclear medicine products, they faltered commercially because medical oncology doesn't typically want to hand over a patient to nuclear medicine. And so getting that balance right commercially and getting that positioning right is super important. And we've finally seen some breakthrough with that PSMA. That said, our view is that a small molecule is a really inefficient way to deliver a therapeutic radionuclide.

90% of the injected dose is excreted and essentially in first pass renal clearance. And so using a biologic means that we can use much less injected dose. Typically, our entire course of therapy is about 1/10 of the injected radiation dose and has really profound impact in the way in which you manage a patient in the outpatient setting.

And the use of a PSMA targeting antibody engages with PSMA completely differently than a small molecule. It internalizes differently. The radiometal is charged, trapped in the cytoplasm of the cell where it decays, it stays there. If you take a small molecule PSMA agent, and you scan a patient 3 days later, there's nothing there.

If you take 591 and you scan a patient 3 weeks later, it's a decay-corrected scan of kind of day 1 or day 3 because the antibody has a circulation time. So the whole radio biology of 591 is completely different. And the dosing is different. So 591 is 2 shots, 14 days apart. That's the end of study end of treatment. And that's really important from a patient compliance perspective.

It's not all up, including follow-ups and observations, it's not 40 weeks of therapy, 2 weeks of therapy. So it's a short detour into nuclear medicine, then the patient goes back and continues their RPs and their PARPs or their taxanes or whatever else they're going to ultimately get in combination with a radiotherapy.

And we think that makes the therapy much more amenable to prescription from a met on. From a patient perspective, we don't have acute nausea and radioactive urine and radioactive vomit during the infusion process. We have patients that turn up to get infused, they cycle there to get their infusion and then they cycle home afterwards.

That's not the hallmark typically of getting a competitor product infusion, right? And then because it's a biologic, it's a macro molecule that doesn't penetrate basement membranes and tie junctions the same way that a small molecule does, we don't get some of the off-target effects. And we do get cytopenias because it's an antibody. But this is a clinical AE.

This is not a patient AE, right? This is something that you -- no one goes home and says, "my neutropenia is acting up today, right? So it's a clinical AE that medOcs, by the way, are used to managing. And it's not an acute -- it's a predictive very well, very -- at day 7, you can tell at day 21, whether you're going to need to 15% of patients or so are going to need a platelet infusion. So this is a very transient, reversible self-limiting. And so we don't see it as problematic, but what we do get is a benefit is we don't get the salivary gland uptake, the lacrimal dry eye, dry mouth, patients just feel a little less banged up.

And so we think that through the combination of the infusion protocol, the patient-centric kind of nature of the product, we hope -- I mean, efficacy being all things equal, that it would be -- it will just be an easier product to use.

Yes. No, I definitely like -- it seems to be more palatable for patients, which is definitely more convenient, especially also from a dosing schedule perspective as well. And when we think about the competitive landscape, obviously, I think about the Convergent compound, right, which is the exact same targeting moiety, correct, except using Actinium, but you are also advancing TLX592, which is a modified version of the J591 antibody to enhance clearance. I think there's better biodistribution as well and you're using Actinium as well. So it seems like you're making another leap forward on that front.

We know a lot about 591. I mean, Virgins does too, it's Neil Bender's company. We had the opportunity once upon a time to put actinium on 591. And we just don't -- we think that when you have an alpha -- and one of the consequences of an antibody is you're perfusing all your organs for a prolonged period of time.

That is not the ideal carrier for an alpha emitter. So we think -- so the good thing about putting Actinium on 591 is that it's hepatically excreted. So you're parking -- you're not parking the alpha in your kidneys. My personal view, and I know there's a lot of disagreement about this, but alphas have no business being on small molecules because alpha decays in your kidneys are very challenging to recover from.

And we see a lot of latent nephrotoxicity. So I think parking excess radiation in your liver, which is the hallmark of an IgG is a good thing. 592 is a PK engineered, Fc engineered antibody that has a much more rapid blood clearance. We've done clinical work. We've shown that the antibody clears faster, and so what that means is just less alpha decay events in circulation, and that's less likely to have issues for the patient.

And the challenging thing with alpha is because of the path length of alpha decay, I don't think people really believe that alpha therapeutics are going to be great in bulky disease. I think the thing about alpha is really in the burden of disease. And that means that when we do inject an alpha meeting radiopharmaceutical into upstream patients, we need to be confident that they're not going to have long-term consequences to it. So the alpha space, whilst it's exciting, it's got a super long ways to go.

Yes. I think one of the places where alpha sort of where it has its potential is in the post-beta emitter portion as well just because of the nature of alpha emission. You could also use it concurrently with a beta emitter, too.

Yes, there's been some evidence that, that works.

Yes. Why don't we shift gears a little bit now because there are a few things...

Do we have time.

Yes, we still have roughly 7 more minutes.

Okay, sorry. I...

So when we take a broader view, there's obviously been a debate around targeted radionuclide therapy as to whether it could be as large as the ADC field has been. Obviously, we've seen great success in ADCs. And it seems like a lot of targets from the ADC fields can be used within the radiopharma space. So I wanted to get your thoughts as to how you view the target landscape broadly from a radiopharma perspective?

Yes. We have a lot of pretty heated conversations about this internally. I think it would be a miss for radiopharma to go after just the same old target that ADC world goes after. That said, the radiobiology of radiobiology is different than an ADC.

And the whole mechanism of action is different. People just think of radiation sometimes as another cytotoxic payload, but it isn't. There are multiple mechanisms of action involved in radiating the tumor microenvironment. And that's -- and the key word in that is micro environment. So I think that actually there's a lot of scope for ADCs and radiopharmaceuticals even against the same target to work in concert with each other.

Certainly, the imaging portion will have also value to the ADC part as well. So I think that it's not an either/or. I would like to see, and we are spending time and energy on looking at more and more targets that we think are and substrates that we think are uniquely beneficial to radiation. And there are targets that would be kind of much better suited to radiopharmaceuticals than in ADC.

Yes. So last question for me. So obviously, Telix has built and acquired a broad portfolio of radiopharmaceuticals assets the manufacturing, distribution and research spectrum. So you've been very active on the BD front. So moving forward, could you give us a sense as to what types of technologies you're most interested in acquiring?

Yes. Well, we're actually just -- for early next year, we're going to be putting out -- our business development team is actually going to be putting out a kind of a manifesto that says, "this is what we are interested in, this is what we're not interested in because we've actually grown to the point now where we are viewed by many companies, smaller companies as a potential go-to-market partners, possibly not if we have too many more CRLs.

But if you're not -- at least if you're getting CRLs, you're like trying, right? So I suppose that's something. But I guess from our perspective, we really actually have -- we've built 3 pillars of assets in the company now. We've got a great R&D portfolio, and it's about 14 molecules, diagnostic and therapeutic there enough, frankly, to keep us going for a long time.

And then the second asset that we're building is really that vertical integration of manufacturing and supply chain, which by the way, also lowers CRL risks as well because you're really in charge of your manufacturing CMC, and we think that's vital. Like we think that going forward, you just -- you won't get into a Phase III program as a radiopharma company unless you really can command some of that infrastructure.

And then the last pillar of our business that we're building is really the commercial team. And it's a bit unusual, but we do sell our own products. And not a small indication, prostate cancer, it's not a small indication. And we do that because we really think that these products are unique. So when I think about what are we interested inorganically, I mean, frankly, we're digesting a lot at the moment. I mean we've done $0.5 billion worth of acquisitions in the last couple of years, which probably for the big pharma guys doesn't sound like a lot, but for the smaller -- for a small company, we're only about 1,200 people, it's a lot.

But when we think about what would be the growth engines, it's really very, very novel early-stage preclinical stuff. That's the pipeline of 5 to 7 years from now. We are still interested in isotope platforms. So we have a Lead-212 generator in development. We are doing actinium production in-house. So we are doing these things. And then obviously, also the commercial team is something that we continue to invest in. So those are sort of the 3 buckets of kind of go-forward investment for the company.

Okay. That's really all the questions I had. Christian, thank you so much for joining us today.

I appreciate the audience. Thank you very much.

Okay. Good afternoon, everyone. We're here with the second last session of the day. My name is David Bailey. I'm part of the Australian health care team at Morgan Stanley.

Before we get going, I just have to read this out quickly. For important disclosures, please see the Morgan Stanley research disclosure website at morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative.

So welcome, Dr. Chris Behrenbruch, CEO of Telix. Maybe just for those who are a little bit less familiar with your company, just a bit of an overview. A bit of background would be great as a starting question.

Yes. Thanks, and thanks for the opportunity. So we're globally active, I guess, you call it a pure-play radiopharmaceutical company. We are a commercial stage company, a little bit unusual in the sense that we have a deep pipeline of products, and I'll talk a little bit about that more in a second, but we are commercializing our products as well in the major markets we serve. We're clinically and commercially active in 26 countries.

We have sort of 3 pillars of value creation in the company. We have a portfolio of products that target what we think are exciting targets in cancers and rare diseases, where we target that we go after. We develop both an imaging agent and a therapeutic because we think that, that precision medicine strategy is extremely important. And in fact, it's the whole point of radiopharma. You know where your drug goes because you can measure it. You can put a patient in the scanner and you can see everywhere from your toes to your nose where the drug goes, terrible literation, but anyway.

The second pillar of value creation is we're a vertically integrated manufacturer of products. We rely heavily on a partnership distribution model in almost every market we serve, but we also see that the future of therapeutic drug development in radiopharma is very infrastructure intensive. And so we've made about USD 0.5 billion in investments over the last couple of years to really make sure that we are along with select partners in control of our destiny. And we think that's critically important.

And then the third thing, as I mentioned before, is that we are commercially self-powered. So we go out and sell our own products even for a major indication like prostate cancer, which is where our lead programs are because we think that selling radiopharmaceuticals to oncologists is a unique thing. It's a very content-rich sell. You're not just selling a vial or a blister pack, you're selling an entire clinical service from how do you manage your practice, how do you dose patients, how do you calibrate cameras, how do you do waste management. And we think it's really important to be part of the care team. And so we take a really service-oriented viewpoint, and that's why we put ourselves out in front as the commercial partner.

So those are the 3 parts of our business. This year, we'll do about USD 800 million in sales. We fund about $200 million in R&D of earnings. So over the last few years, since we commercially launched in '21, we've become a cash-generative, profitable business and really focused on now extracting the next value of inflection points from our pipeline. So it was a bit of a long-winded answer, but it is a bit of a complicated business, and those are the key parts of it.

No, it's a good introduction, good segue to my follow-up question. So you mentioned 2021, '22. It's been very rapid. We are at a stage now where you are generating cash flow and reinvesting into the business. So just what does that look like over the next couple of years? And then part of your R&D Day presentation, there is a pathway to profitability and balance sheet position. How do you sort of see that evolving over the next couple of years?

Yes. So we're lucky because we really are a classic biopharma company in the sense that our sole focus really is to build out the value in our pipeline. We've got an incredible pipeline of molecules. We've got basically 14 molecules across our diagnostic and therapeutic pipelines. We have -- and those are our clinical stage programs, not even counting things that are sneaking in behind in 4-legged patients instead of 2-legged patients. And so our latest-stage therapeutic program is in Phase III. We've got a couple of other Phase III trials kicking off. We've just had a run at 2 drug approvals for 2 more diagnostics. So we had some minor setbacks with the FDA that we're in the process of rectifying that there's some real unlock value there coming up.

So really, what I'm talking about there is pipeline, pipeline, pipeline. It's just that we happen to be able to invest in our pipeline ourselves from our earnings. But sometimes we get mistaken for being a health care company, and we're not quite there yet. I think that 2027 is our pre-commercial launch year. 2028, we hope to be selling our first therapeutic drug. There are a couple of candidates to kick off in 2028. That's when we really start to see that the cash generation ability outstrips our immediate R&D needs. But until then, it really is about, albeit with some cash buffer and some contingency management on the balance sheet, it really is about all in on the pipeline and to have as many programs as we can in late-stage development.

And strategically, it's self-funding as opposed to looking for partners. So just to be clear in terms of your business model, it's the cash you're generating from the approved products, reinvesting back into the pipeline.

That's right. I mean, we have conversations all the time with potential partners. And I'm not ruling out the possibility at some point. But the value proposition of partnerships tends to be around manufacturing and supply chain and commercialization. And as I sort of said, we think that manufacturing and supply chain is unique in this industry. It's not something that you can go to a [ brown brick pharma and solve.] And we think that the commercial interface to the patient is also really unique. And so we just don't see that as a value proposition that you're going to immediately get out of the pharma partnership.

But that said, of course, there's been a lot of transaction activity in the space, and big pharma is certainly interested, big and medium-sized pharma is interested in radiopharma and it should be because I think it's going to be one of the key pillars of cancer care and other areas, frankly, in the future.

Understood. Maybe just on to the PSMA imaging market. So just an overview of the current approved products. And maybe just sort of what you've been seeing in the market more recently from a competitive dynamic or market perspective?

Look, there's no doubt, I mean, the PSMA opportunity, I don't think anybody really imagined how big it would be. I mean even I'm fairly ambitious, my team is fairly ambitious, and it's kind of it's bigger than everybody expected, but it's also going to get bigger because it had such a profound impact on prostate cancer care and is across the patient continuum. That's really the first time that we've seen molecular imaging just show up all along the patient journey for a given disease.

It's -- longitudinal imaging hasn't been that big a part of cancer care in the way that it has been for prostate cancer. And that's just because the decision-making that you get at each point is so unique. You've got a high-risk patient, you want to know, do they have disease. You've got a patient that's being staged for surgery, you want to know how far to cut. You got a patient that's had a surgery or radiotherapy and has a rising PSA, you want to know where the disease is. You have a patient that's on an expensive drug regimen, you want to know are they still responding. These questions are so distinct and yet it's the same product that can give you that information.

So we're sitting at about 80% penetration of a $3.5 billion market. We see -- in the U.S. alone, we see the opportunity for that market to double over the next 2 or 3 years through indication expansion and label expansion. And it is a maturing market. So now there are 4 approved products in the market. We do expect to see 5 and 6 and maybe 7 come to market over the next couple of years. But it's also clear from the current competitive dynamic that it's going to be harder for new entrants to get in. They're going to have to catch up on label. They're going to have to catch up on distribution infrastructure. They're going to have to catch up on -- I think unless there's a profound clinical value proposition, it's going to be really hard to compete. And we always have to remember that it's a $3 billion market, right? But it's with a product that sells for an ASP of, call it, $5,000 and has gross margins of 60%, right? So the impetus to get into the space in a very -- it's a very specialist space, I think, is not the same as for a therapeutic drug.

So I think it's a specialist market. I think the distribution infrastructure is a specialist. It is becoming more commercially competitive. We have seen some price erosion, but that's just to be expected in a maturing market. What I also believe is that in order for us to reach the potential volume of sort of 2 million scans for PSMA, you've got to have a different price point anyway. So it's one of those things where to achieve -- to realize the full market, you probably going to need to have a slightly different price point anyhow. So it's a volume game. And clearly, the firms that can scale are going to win because it is a volume game. This is not a -- it's not a rare disease indication, right, where you're going to service 10,000 patients a year, and that's it. This is a large-scale mass market indication.

I will move on to the potential expansion of the market in a minute. But just -- maybe just talking through your existing product portfolio, so Illuccix and Gozellix, 2 slightly different products there. Just talk us through the slight nuances between the 2. And then how you're seeing the opportunity for Gozellix last quarter this year and into fiscal '26?

Yes. So it's clear from a reimbursement perspective that we are now -- because of the way that you get pass-through and your HCPCS code, we're in a cyclic innovation environment. And that's not uncommon. I mean it happens in other parts of pharma as well, right? So -- but essentially, ongoing product incremental improvements are going to be necessary. There's going to need to be innovation to get new product reimbursement. And I think that's good broadly for customers as long as we continue to do clinically added value innovation.

Gozellix is a significant improvement on Illuccix. It offers a couple of things. One is about a 3x longer shelf life, which means that when we manufacture it, when we compound it in a radiopharmacy, we can drive it further. We can service more customers from our pharmacies. And it also means that we can do very large scale production of gallium-based products and deliver that into the hospital environment, which has been traditionally a kind of strength of F-18-based cyclotron products. So today, drinking in Diet Coke are the same -- [indiscernible] and Diet Coke at the same time don't work. So cyclotron-based products have purported to have that edge. And I'd say that in some academic environment, that's an advantage, and we can go in now and we can solve that problem.

And the third thing that we did with Gozellix, which really has huge implications for the industry was we were able to convince the FDA that we can go from solid target production of radio metals like gallium and zirconium and copper-64 straight into the nuclear pharmacy. When we had this conversation with the FDA 5 years ago with the Illuccix, it was no. You have to bombard your target, you have to do the dissolution and produce your radio metal and then you have to do radionuclidic profiling of your radio metal before it goes into practice of pharmacy. That's a big deal that just basically pushes you into GMP manufacturing territory like a classic cyclotron-based approach. With Gozellix, we go straight from cyclotron to pharmacy, which means that it has a big implication for cost of goods structure. The volume of demand you can satisfy. And it really changes the model for cyclotron usage.

And so all of those then wrapped up in a new reimbursement code because we are delivering clinical innovation. We're delivering better scanner throughput. We're delivering to patients that are in radiopharmaceutical deserts that aren't being serviced right now. We think about 15% of the market. It's never -- 400 PET scanners have never tasted PSMA of any kind because the planes, trains and automobiles that our competitors have to take to get a dose to a patient prevents it from happening, right? And so at least happening cost effectively. And so that's what Gozellix gives us. And HCPCS code goes into effect 1st of October. We're expecting to get pass through. And it's a big advantage to patients. So we're really excited about that.

So it's a volume game, potentially moving to markets you haven't played in before, but then also distribution into places that haven't actually received your products in the past. So that's from a volume perspective, have I got that right around that?

Yes. And it's pricing as well. The Gozellix, we will seek value for the improvements that we've made in the product. It has a little bit of a dosing -- dose price strategy that's different as well, which confers an advantage to the product in the reimbursed setting. So yes, we expect Q4 to be a significant event for our PSMA franchise overall.

And how important is transitional pass-through pricing. I know it's relevant to a subset of the market. But is that something that's kind of important, material impactful? Or is it more of the fact that you've got a product you think you can price a little bit differently relative to Illuccix that's more important for the overall revenues?

Well, I think there was -- historically, there was a lot of focus on pass-through because when pass-through was finished, you went into a bundled procedure code and it was perception that there was this kind of Armageddon event. And in practice, what you did is you sat down with your customer and you segmented the components of their CMS, the 340B, their commercial patients, and you came up with an average pricing that kind of made them whole. And so the net result is it was the price erosion, not a catastrophic price erosion, but it was a price erosion.

The CMS reform that happened at the end of last year, which is now that diagnostic radiopharmaceutical above a certain price threshold have stand-alone pricing has kind of taken the importance of TPT away, not completely, but mostly. So the fact that you have a new HCPCS code means you have a reimbursed product, which means that you essentially get all the benefit competitively.

The TPT confers one last advantage, which is that for the proportion of Medicare patients, not all, but it's a proportion, there's a -- the co-pay is eliminated under TPT. It's -- it doesn't apply to Medicare Advantage. There are plenty of patients that have coinsurance on that. So it is -- for us, it's a single-digit proportion of our business that's really ultimately benefited. But I would say that it's -- I describe it as a kind of a hygiene factor when you go to a customer that you're trying to competitively acquire and you have TPT, it's a good tick box. It does help with customer acquisition.

So we hope we get it. But if we don't get it, and I'm not complying that we think we won't, we'll find out in the next couple of weeks. We meet all the criteria for it. But the most important thing is that we've got our HCPCS code that opens the door to that market segment again.

And in terms of life cycle management in this space, and I'll move on to bypassing a second. But you made an announcement recently of another potential product. Maybe just talk us through that one a little bit more how that's kind of different.

Yes. So we think that there is -- we believe that physician preferences exist and it's something that new entrants into the field will also have to think about. We worked really hard to establish Gallium PSMA. A lot of people thought Gallium PSMA would never be successful. I had major key opinion leaders in the U.S. say it's a European thing. It will never take off here. When we do PETs, we do F-18, okay?

And there is a fairly entrenched thinking around that. If you look at physician workflows, and I'm not an armchair CEO, I really love to get out to the field. I spent a lot of time, in fact, I see some of my business partners even in the room. I spend a lot of time out talking to our customers and visiting our customer sites. And when you go into a large, busy hospital, efficiency and workflow is really important. And so when you're doing FDG scans all day and then you want to weave in a little F-18 PSMA in between, it's really convenient to not have to change your scanner calibration settings. You don't have to change your windowing and your workflow on your workstation. It's just conducive to volume.

And also, I don't remember which analyst it was that made the analogy, but in the academic centers, Telix tends to be the morning espresso. And then at 11:00, the big bucket of Starbucks coffee arrives from Lantheus. And I like that analogy because Starbucks coffee tastes like s***. But anyway, so the Starbucks coffee arrives at 11:00 and academic centers love that because it's -- there's a volume of material there. They know it's there. They're not waiting on scheduling throughout the day. It's different for an IDTF. They don't have a dispensing nuclear pharmacy. They're receiving doses all day. They're used to that. But in an academic center, it's different.

And so because of these workflow considerations, I do think that there are some users that do just say, "Look, your product is great." They may even buy into the fact that we have the best sensitivity and specificity and the best inter-reader variability, but they kind of just like what they like. And so the [indiscernible] product, when you -- turns out when you react aluminum or aluminum as it's known in these parts with F-18 or with fluri, we get a molecule that looks and behaves exactly like gallium-68, to drop in replacement for gallium-68. You have the same targeting agent, same chelator, same formulation, same lyophilized vial, and you can just drop a big glob of aluminum fluoride into it. And you can dispense Illuccix basically, but flavored as F-18. And so that enables us through the nuclear pharmacy infrastructure that we built to, at a cyclotron site, very efficiently produce aluminum fluoride under a drug master file and then drop it into a pharmacy and then dispense an F-18-based dose. And it really has a lot of the same advantages that Illuccix and Gozellix has.

So it's, again, part of our ongoing life cycle management. It's about thinking 3 years ahead. We have a Phase III trial that we acquired as part of the IP. That includes intrapatient comparison between Illuccix and aluminum fluoride. We've taken that to the FDA. We have advice on what does the bridging study needs to look like. We'll do that study next year. We'll complete that study next year. And hopefully be in a position to file an NDA for that product at the end of next year. So that will be then -- I guess you can think of that as Gozellix version 2.0, but just minty flavored.

Maybe just -- that's great. Moving on to maybe the potential expansion of the market. So the approvals in the prostate protection space, staging PCR and RLT selection. Maybe just help us understand what -- you sort of mentioned the dollar number there, maybe a number of scans, if you can in the U.S., but then also moving on to the BiPASS study and what that could do in terms of number of scans, a potential market opportunity there.

Yes. So it's about a 700,000 scan, 3 billion odd. Everyone's TAMs very slightly, but I think that, that's sort of ballpark, right, defensible number. We're sort of 80% penetrated that number right now. So that's the current market opportunity. The growth areas really come, I think, from a couple of specific things. We are seeing continual guideline evolution that does flex a little bit the interpretation of what's the BCR patient or high-risk patients.

And as we learn more, the great thing about PSMA imaging is we're just learning a lot more about prostate cancer and prostate cancer risk. We used to think that a Gleason 6 or 7 patients was a high-risk patient. And now we see at least in 4 patients with certain histologic subtypes that are metastatic. So we're learning more, and that sort of flexes the appetite, I guess, in the existing indications that we have.

The other thing is that on the therapeutic side, not just driven by Novartis' success in radioligand therapy, but many other prostate cancer drugs, including ones that are in clinical trials. We service a lot of those clinical trials because we're one of the few people that can deliver a dose globally. So we see a lot of that trial activity. We're seeing PSMA imaging really used in longitudinal management of patients. And it does make sense. It's going to get to the point where, let's say you're doing an expensive radioligand therapy and it's 6 cycles of therapy, you're going to want to know after your second to third cycle, like are you getting patient responses. I think payers are going to want to know that information. So there's going to be more and more use of longitudinal imaging there. That's a multi-imaging time point opportunity. And so that will increase the market size by, I don't know, 20%, 30%.

And then the other opportunity is really at the front end. So we just launched a Phase III trial called the BiPASS study, as you mentioned. This is not about eliminating biopsy. This is about making sure that when you biopsy a patient that you should be biopsying a patient. So we do over -- we do about 1.2 million scans a year -- sort of 1.2 million biopsies a year in the United States, about 800,000 of them don't really add value. So the idea of the BiPASS study is to use PSMA imaging on top of MRI to stratify whether a patient should be scanned and done. There's no reason to biopsy a patient based on cumulative PSMA and MRI information or scan and one. So given the focal targeted biopsy, minimum number of tissue samples, use the image guidance to really sample the correct part of the prostate and be confident and grade better. Or if that's all sort of ambivalent, then go into a template biopsy.

And so we think we can stratify patients that way that can add another 750,000, 800,000 scans. But it's also strategic because there's a truce that when a patient is first scanned with a particular flavor of PSMA, they tend to want to continue that flavor in time so that you can get like-for-like comparisons. And so it's also about strategically moving upstream. And whoever can move upstream the furthest ultimately kind of wins the overall price.

And what's the timing around that one?

So we started the study -- it's going to be a pretty fast recruitment. It's only 200 patients. It's something that academic. There's actually a couple of wonderful studies that have been done in academia that show this as a proof of concept. So there's appetite to do it. When we've got great centers recruiting, it should take us maybe 6 months to recruit it. Probably, it's another -- there's a follow-up period just to make sure that we're not introducing false positive, false negative into the decision-making tree or to be able to characterize what that risk is. So I imagine that we should be able to file that as a label extension next year. And that will then come into effect in 2027. Again, part of that sort of 2-year life cycle management plan.

Maybe just moving on to therapeutics. Just give us a -- can you just give us a bit of a sense as to the pipeline and what you're really focused on at the moment?

Yes. So we have kind of 3 concentration areas in the pipeline. So we want to have a long-term stakeholder relationship with urologic oncology. That's obviously cornerstone by the prostate cancer program, but we also have a very late-stage renal cancer program. Imaging clinical work is done, therapy. We're hoping to take that into Phase III this year as a monotherapy in advanced metastatic patients. And we're just going backwards and forwards with regulators right now on the protocol for that and trying to decide whether we need to get more data from our second -- our Phase II trials or whether we have enough data to move ahead. Principally, the issue is safety, obviously, to have enough safety data. So yes, that's very exciting.

Our IPAX-BrIGHT study in glioblastoma is just kicking off. That's a pivotal trial, starting ex U.S. and then hopefully adding U.S. patients as a cohort expansion just because the standard of care is a little different in the U.S. than it is in other parts of the world. So we're excited about that. So neuro-oncology is really an unmet need. We've shown some really encouraging data. And we've shown prolongation of life even in recurrent glioblastoma patients. We've seen good evidence of antitumor response. So we see that as a second potential area aside from urologic oncology where the company can do well.

And then we have, I broadly call it a musculoskeletal franchise. It's around things like sarcoma, osteosarcoma and bone metastases. This used to be a very well service part of nuclear medicine. It used to be an area that nuclear medicine did a great job in. And we sort of lost the art a little bit, and there's some need for some improved products given the number of patients that are getting radioligand therapy. We'll ultimately progress with advanced bone metastases. There's a need to transition those patients into palliative care without pain.

So we see a really interesting opportunity there to sort of bookend the radioligand space and use that as an entry point for the business. So those are the sort of 3 main areas. We acquired a FAP program last year or early -- going into early this year that's got a lot of patient data, patient data in hundreds of patients. So we think that can go quickly. So just a lot of things that are in advanced development that have good clinical data underpinning it.

One looks most advanced is probably the ProstACT GLOBAL. So could you just give us a bit of a sense as to where we're at now. So I think it's part one fully recruited. Just what that looks like versus the second part. And then how you think it's different to approve products?

Yes. So ProstACT GLOBAL took us a bit of extra time to recruit that we hadn't anticipated. And the reason for that is kind of twofold. First of all, it's a full safety dosimetry study. So it's multi-time point SPECT imaging. It's really demanding on the patient and the site. And actually not a lot of sites have the sort of physics chops to do it properly. So we actually limited recruitment to a small number of sites to try to do the study well, and we just didn't have the recruitment volume. Like I said, it's more of a science project than a medical oncologist referral sort of dream, right? But now that it's done, we're expecting to read that data out in a couple of months' time. It's fully recruited.

The docetaxel arm has a slightly longer kind of observation period than the RP arm. So it will come a little bit later on, but before the end of the year, we expect to read out that part one. And that's a gating study for the FDA. We want to see that the safety profile across the 3 proposed treatment arms of enzalutamide, abiraterone and docetaxel that they are equivalent in terms of safety profile.

Ex U.S., we don't have that challenge. So the study protocol is approved in Australia, New Zealand, Canada, Turkey, China, Japan and I'm forgetting one -- Singapore, I think we got last week. We've got Europe planned later on this year as well. And so the part to the randomized part of the trial, it's a much more vanilla study. It's pretty straightforward, 2 shots, 14 days apart, just conventional imaging for patient selection. So it will be a pretty fast study to recruit. We're expecting to have about 60 sites, 70 sites up and running by the end of the year. And we expect to substantially recruit that study by the end of next year. Certainly, the futility analysis, which is based on 90 events, we would hope to have that done by the end of next year or maybe early '27. So that's the time line on that.

A ton of investigator engagement on the trial. The value proposition is really compelling for medical oncologists. It's a very simple dosing regimen, 2 shots, 14 days apart. That's the entire course of therapy. So high patient compliance, essentially a single toxicity event, which is the challenge of doing competitor radioligand therapy. It's essentially with all follow-up and everything. It's about 40 weeks of therapy. That's a long time in the life of the metastatic patient and compliance does tend to fall off after a few doses.

We don't have salivary gland uptake or dry eye. Patients don't feel has banged up. The amount of radiation that we inject over the course of therapy is about 1/10 of the current approach. That has all kinds of consequences around ambulatory patient management, injection characteristics, don't need toilet for radio activity. You don't have to worry about radioactive vomit. Tend not to have a gastric reaction that the small molecules have. The downside is we do have some cytopenias. It's very typical of using an antibody-directed therapy, but they're predictable, they're manageable. It's about 15% of patients have a Grade 3, Grade 4. You know at day 7, whether you're going to need to give a platelet transfusion at day 21. So it's not an acute event. It's a predictable event. And it's transient, and it's recoverable.

So these are clinical AEs. No patient goes home to their partner and says, "My neutropenia is acting up today." These are things that physicians have to manage. And because we're targeting our product at medical oncology, medical oncologists, we've had tremendous success in radioligand therapy when it's been used in the last line setting. Now as it moves -- we all want radioligand therapy to move into earlier lines of therapy. It should move into early lines. It's very synergistic with patients that have their clinical capacity to respond. I'm confident we're going to see synergies with checkpoint inhibitors. We're going to see synergies with parts, with even taxane. Taxanes are a great radio sensitizer. I'm excited about the docetaxel arm in prostate global because I think it's important for many parts of the world where that is a standard of care, that's going to be really important to show benefit for patients.

The challenge is that when a course of radioligand therapy is managed by a theranostic center or by nuclear medicine department, that's essentially the medical oncologist handing over the patient to another specialty. And we just -- it's not everywhere a limitation to adoption and properly integrated cancer models will allow it. But in a lot of places, there will be a conflict around patient ownership. We've seen it happen in nuclear medicine before. We've had product sale in nuclear medicine because [med-oncs] will not refer patients to another specialty. So what we believe is that the best way is to develop very focal, very condensed time line therapies, intense therapies, high patient benefit that medical oncologists can send the patient to nuclear medicine for a couple of weeks, and then they'll come back and they'll continue their taxanes, their PARPs, their RPs, whatever. And it's just a more effective prescribing model.

We've got about 45 seconds left. So I do have a few more questions, but I'll -- the final question I might just ask you is, what do you think the market, us as sell-side analysts, investors are not paying enough attention to?

Everything except the Illuccix business. I'm kind of bored of talking about prostate cancer imaging. I didn't actually start the company to do prostate cancer imaging. It just sort of happened along the way. And I'm glad it did so don't get me wrong, but I think our market cap is kind of below the enterprise value of the Illuccix right now. And I think we all know why it's a challenging environment. But it's also -- we're a very ambitious company. We have 3 drug approvals planned for this year. We've got 1 over the line. We've got 2 more to come, and they will come.

The challenge with radiopharma is it's a totally new area. As everybody is learning in real time, including the FDA. No one's ever submitted a biologic-based pet tracer to the FDA before. So there's some definite learnings there. But really, the upside in our pipeline is just huge. So I think the entire commercial dynamics around the business and the investor appetite really today is just focused on prostate cancer. I think if we can just get a few of these other products over the line, and maybe regain some trust that, yes, yes, we can deliver other products to market, and I think we'll be in a really good shape. But that's what the market is missing today is the potential of that pipeline.

Understood. That does put us at time. Thank you very much for your time this afternoon.

Thank you.

Please join me in thanking Dr. Behrenbruch.

Cheers.

Thanks very much. Good morning, shareholders, analysts and colleagues. Good evening to those dialing in from other time zones. The purpose of this call is to address the disclosure released to the market this morning regarding our FDA biologics license application for TLX250-CDx provisionally designated as Zircaix. Unfortunately, per our disclosure, we have today received a complete response letter or CRL from the U.S. Food and Drug Administration in relation to our drug approval application.

This is clearly not expected or positive news, and we want to give the opportunity for Q&A and engagement on the topic while noting that there isn't a huge amount of additional information to share at this early stage. In short, we've received the CRL on the basis of three highly related issues. The first is a series of Chemistry, Manufacturing and Controls or CMC topics. These are, for the most part, fairly straightforward issues that reflect the overall complexity of the manufacturing package for Zircaix.

The second somewhat related issue pertains to inadequacies in demonstrating comparability between the drug product used in our highly successful ZIRCON Phase III trial and the scale-up manufacturing process that Telix intends to use for commercial use. Third, the manufacturing and supply chain for the product is very complex and relies on a significant number of third parties for delivery.

This is, in fact, part of the reason why Telix has been so focused on building and internalizing much of this capability in-house, to streamline and better control the process around our commercial manufacturing activities. Two of our third-party suppliers received Form 483 observations during recent site inspections, and the FDA has asked that responses to those 483s be resolved prior to resubmission. This is a fairly standard process when there are identified CMO and supplier deficiencies.

The feedback from the FDA and the CRL is detailed and useful and reflects a high degree of engagement around the product, reflective of its breakthrough status and the priority review we were granted. A number of the CMC and comparability issues outlined by the FDA in the CRL were actually part of post late cycle review submissions and responses to information requests from the agency, but were apparently not reviewed in time for the PDUFA goal date.

This is one of the challenges of a priority review process because it's a really tight time line, but we are confident that we can address these issues and remediate the application fairly quickly. Per our disclosure, we will immediately start work on a Type A meeting request to address all the issues raised in the CRL. I don't have a determinate time line to give you at this stage, but it shouldn't be more than a few weeks to prepare the briefing document, given all the really superb work the team has done on this package.

From that point, it's up to 30 days to confirm the meeting, and we will, of course, report back once we've mapped out a clear remediation time line based on the agency's feedback on the CRL and of course, the third-party remediation as well. Finally, before I open it up to questions, I'd like to add 2 important pieces of color around where we are at.

Firstly, this is a really novel product. Nobody has ever submitted a drug approval dossier for a biologic-based PET agent to the FDA before, and its novelty also lies in the use of zirconium-89, really defining this as a first-in-class product. We're at the vanguard of developing a new class of products, and we are consequentially being held to a very high standard.

While there are always some things in hindsight that we might have done a little better, a big part of where we are at reflects both this product novelty and overall maturity of the supply chain. As I've said, we believe we'll get it over the line and make it commercially successful, but it needs to be acknowledged that we are also breaking new ground here and speed bumps can and sometimes do occur. We remain fully committed to bringing this amazing first-in-class product to patients driven by the urgency of addressing a significant unmet medical need in renal cancer.

The second thing I want to note for completeness is that this commercialization delay for Zircaix as was the case for Pixclara, does not impact our financial guidance for financial year 2025 as we do not include revenue from unapproved products in our guidance.

Okay. Well, I'll leave it at that and open up to questions from the floor.

[Operator Instructions] The first question today comes from Tara Bancroft from TD Cowen.

This is Nick on for Tara. What are the key differences between the product studies subject to the TLX250-CDx studied in the Phase III ZIRCON trial and then the scaled-up manufacturing process? And how quickly could you generate data to confirm the comparability between the two? And what would that look like? Would that be another trial? Would that just be simple data process?

Yes. We've actually mapped out that comparability activity with the FDA in advance and in fact, had agreed on a road map with the FDA. I think it's going to be a mixture of analytical and clinical comparability. We do have a whole bunch of extra data that wasn't included in the original BLA submission. So I don't feel like we're going to have any really significant time delays to collect new data. I feel this is a dossier reconstruction or resubmission exercise rather than a new data gathering exercise.

Just to answer the first part of your question, from a company's perspective, the changes weren't particularly dramatic. They mostly focused around a more commercial scale production of the antibody as well as a larger specific activity radiochemistry, as you would expect for multi-dose production. But I think fundamentally, as you know, these kinds of comparability nuances are a pretty specialized area from the FDA's perspective. Hopefully, that gives you some useful color.

The next question comes from David Stanton from Jefferies.

Look, I guess -- I know it's going to be very hard, but a reasonable time frame for resubmission, might that be sort of end of calendar year '25? And then, I guess from there, you'll still need a 6-month review process. So at the -- I guess, the earliest, it might be a 1-year delay to getting this product on market. Is that a reasonable way to think about it?

Well, I think it's a reasonable thesis, but we're not giving guidance on time lines until we finalize the time line and the scope of work on the basis of the FDA's feedback. So we'll have that in a few weeks' time. I really feel like based on our understanding of the CRL that this is not a protracted process to get to understanding of what additional info the FDA wants to see in the submission.

I think you're probably aware that CMC-related CRLs are fairly commonplace at the moment, particularly with biologics. So I think that it will be a fairly concise conversation with the FDA. To draw on the earlier question, I think we're not looking at creating vast amounts of new data. I see this more as a dossier construction and clarification issue. And so I think that -- I don't think it needs to be protracted.

We also have a breakthrough therapy designation, which means there's a fair amount of impetus on the FDA to consider our review comments or review submission fairly swiftly. I think -- I want to acknowledge there's been a high degree of engagement from the agency. I mean it hasn't always been speedy or necessarily clear, but it's certainly been a high degree of engagement. And I don't see that as being rate limiting for the resubmission of the application.

And then mainly just a little bit of comfort. The topics that we're talking about don't relate to the clinical component of the submission. So I think that also makes -- the fact that it's all focused around a bunch of CMC and manufacturing issues does also potentially make the dossier review a little more streamlined if the FDA feels inclined to grant us that privilege.

The next question comes from David Dai from UBS.

Just on the 2 manufacturing and supply chain partners that you're dealing with where -- they received the notice of deficiencies. Could you maybe put some color around who are the partners? And what are some of the remediation procedures and process that is required for resubmission process?

Yes, we wouldn't typically disclose those third parties unless we were compelled to do so at this point in the process. There may be a future point in the process where it makes sense for us to do that. I don't have personally color to give you on those deficiencies or what the classification of those deficiencies may be.

My perception is that Form 483s with sort of the typical observations that we're dealing with are fairly commonplace. And it's pretty typical for the FDA to ask for them to be remediated as part of a resubmission. So I don't think I'm highlighting to you an intractable problem, but it is an additional part of the CRL that we think is useful color to give to shareholders and investors and analysts. And that's why we've noted that particular part of the deficiencies noted in the CRL.

The next question comes from Robert Burns from H.C. Wainwright.

A follow-up on the prior question. Can you sort of elucidate whether -- given the fact that there are 2 third-party manufacturing and supply chain partners, does one need to be resolved before the other one is able to complete that deficiency? Any clarity on the sequence? Are these completely independent?

No, they're -- no, they're completely independent. And -- yes, so one is a raw material supplier or I'd say an API supplier, I guess, technically. The other one is one of the processing steps in the manufacture of one of our drug substances. To be honest with you, we are a little surprised that the 483s got kind of roped into the conversation because in some respects, these sort of observations are part and parcel of those kinds of manufacturing activities.

The deficiencies don't relate to -- for example, the critical components of the product like our antibody manufacturing or our final radiolabeled drug product manufacturing. They're really related to things that mostly involve intermediates or APIs. So I think -- again, I don't want to be misleading, and I don't want to set unrealistic expectations. But I don't think that our disclosure around third-party manufacturers is really the rate-limiting step. I do think it's something that will take a little bit of time to get done, but I don't think it's something that's an insurmountable part of the CRL remediation.

Okay. Last question for me. The additional data that the FDA is requesting for comparability, does that need to be clinical? And do you have it at this time point? Or do you need to run a comparability -- like analysis like Phase I study to do that?

So we have quite a bit of additional comparability data. It's analytical comparability, it's in vivo nonclinical and it's clinical comparability data that is not currently factored into the FDA's analysis of our BLA. And we did some extra work in parallel to the BLA because we had anticipated that when we submitted the dossier in other jurisdictions -- other ex-U.S. jurisdictions that we might get asked some difficult questions, and it was based really on our sort of nuanced understanding of how different regulators see biologics.

And so we did extra work. And so we have extra work to give the FDA that they have not reviewed in a fulsome fashion. There is a possibility that they may ask us for additional data. We will not know the answer to that until we have the Type A meeting with the FDA. But we have a lot of extra stuff we can put down on the table that I think is meaningful and relevant to the conversation.

So again, looping this back down to time lines, I don't see a protracted resubmission time line because we have to go and run another substantive clinical trial or something like that. I don't see that as the reality of the situation at this point in time, based on the information that we have with the caveat that we have not had that Type A follow-up meeting on the CRL yet. So hopefully, that gives you a bit of extra color.

I've another question, but I'll hop back in the queue.

Well, I don't mind. It was a pretty succinct question. So why don't you fire away while you're there?

Okay. So obviously, the FDA has requested additional data. Are they requesting clinical data specifically?

No, not specifically, but there is -- but on the comparability data, it's going to be a fairly wide-ranging question. So it may -- may be that it requires additional clinical comparability data. We do have additional clinical comparability data that we can give them. It wasn't in the scope of the initial comparability work that we had agreed with the FDA, but we did it anyway because we wanted to be ready for other regulators. So we'll just have to see whether what we've got is adequate to meet the FDA's needs.

The next question comes from Dennis Hulme from Taylor Collison.

Chris, can you just clarify the time line that you expect once you've resubmitted the application? Is your expectation that the review would be 6 months from the date that you resubmit the application?

Well, we don't know because we haven't agreed with the FDA what sort of priority or expedited review status we might be eligible for, given that we have a breakthrough therapy designation and given that we were granted priority review. Their willingness to review the dossier on a more streamlined basis may also depend on whether they're willing to look at just the changes that are relevant to the CRL or whether they will take a more holistic approach.

So we'll get some guidelines around that potentially from the Type A meeting. And we'll certainly -- again, I really want to stress the next stage in the process is really to have that Type A meeting to understand where we've got sticking points that are going to have longer remediation times. And then we'll be in a position, I think, to really update the market on what the time lines look like.

The next question comes from Andrew Paine from CLSA.

Look, obviously, this is a second CRL you've had this year, both of which have come as a surprise, obviously, given the products you're putting forward. Just want to know if there's any additional challenges you're seeing at the FDA at the moment. Do you think there's additional pressures given the climate there or yes [indiscernible] getting more scrutinized more thoroughly?

Look, I think it's an insightful question, and I can appreciate you asking it. I also appreciate the implication in your question that there may be more background to our track record than just Telix. The Pixclara and the Zircaix CRL should not be conflated with each other. They're very, very different submission processes. Pixclara, as you may recall, is a -- really a moving of the clinical goalpost for the submission.

I'm not going to go into that particularly today. I think we've addressed that sufficiently in the public domain, and we'll be giving an update shortly on Pixclara per our public disclosures. I think on the Zircaix side of things, it really does come down to the fact that it's a super novel product. I mean it's the first ever biologic PET product. And so you've got different parts of the FDA that don't typically kind of co-review a product -- are reviewing a product.

And I think that's been interesting -- that's been an interesting and frankly, educational experience given that we are one of the few companies developing radiolabeled biologics. So I am trying to be a little philosophical about the situation in the sense that whilst I'd prefer not to learn at shareholders' expense, we are definitely doing a new class of products that will take some learning curve from a regulatory perspective.

And we're seeing that not, frankly, just with the FDA. We're seeing that with all regulators globally and not just for a drug product dossier, but -- or a drug approval submission, but also for clinical trials. I mean, getting clinical trials off the ground in this space, and we have many of them running has been a very steep learning curve. So I think that's kind of my preferred take on answering your question.

I think it's fairly generally known that the world has changed a lot since the start of the year. I think the FDA is certainly an organization that has been impacted by those changes. But I also do want to acknowledge that the folks that we've been dealing with in the agency have been very science-driven, have been, for the most part, procedurally responsive. And so it's on that basis that I'm pretty optimistic that there's a clear platform for us to remediate what are reasonably put forth issues with our submission package.

The next question comes from David Bailey from Morgan Stanley.

Just in relation to the 2 third-party manufacturer or partners there. Is there scope to change to different suppliers? Will you stick with them? Will you look in-house? What's the solution in relation to starting that third-party manufacturing prior to resubmission?

That's a really good question. So actually, for one of the suppliers, we actually already have an alternative supplier that is not at least notionally related to the 483 that was raised. We haven't explored yet whether the FDA's concern is a more general concern or whether it's something super specific. And frankly, I don't have that level of detail in front of me at this point in time. But we have qualified, in that one case, alternative suppliers.

Generally speaking, the suppliers that we've chosen are suppliers that we've built a pretty deep relationship with. And I think our preference, again, based on what we see as the solvable level of severity of these 483s, I think it's just easier for us at this point in time to kind of stick with the folks that we know and the folks that we've been working with. In the fullness of time, if you take a look at Illuccix, for example, when we launched -- when we got Illuccix approval, also admittedly with a small delay.

But when we got Illuccix approved, we had pretty much sole suppliers for most parts of the supply chain. Now today, with Illuccix and Gozellix, we have duplicate suppliers for most parts of the -- or redundant suppliers for most parts of the supply chain. So I think that's something that will kind of necessarily evolve post BLA. I think the goal right now is to just manage the existing complexity that we have in the BLA, get through the FDA's major concerns and then focus on supply chain resilience kind of post approval.

Got it. And just a quick follow-up. Just in relation to the CMC, just confirming that it just relates to the scaling up of the manufacturing process only, nothing else outside of that?

Yes. I mean all of the three issues are all related to the manner and the implementation of the drug product for the commercial package. So there's been no issues raised around the clinical trial material that we used in the Phase III trial. And so this isn't like a fundamental product kind of integrity issue. This is really around what is the delta between the material we use in the clinical trial versus the material that we use for commercial scale up.

And you can understandably imagine that there has to be sort of by definition, some differences in those products they use. They use different grades of radioisotope. They use different amounts of radioactivity because you've got to produce larger batches of material. And that does result in some product characterization differences.

Now, our view as a company, is we submitted the dossier reasonably believing that we had characterized those differences and defended them and that they don't reflect a change in product quality attributes or a change in fundamental clinical attributes. The FDA wants to see a deeper determination of that assertion. And so that's really the focus of the submission. So I think it's really -- as you sort of implied, it's really about that commercial scale of material.

The next question comes from Andy Hsieh from William Blair.

Thanks for the additional information, Chris. So for us, it seems like there are 2 processes, right? So one for the Phase III ZIRCON study and one for the scale of manufacturing. And I'm curious if you can comment on the supply left for the old process, the process that you use to produce the Phase III. Do you have enough to potentially do a clinical-based comparability study? Or you need to go back -- and go back to the old process and produce more drug product to satisfy the FDA's request?

It's a typically solid question from you, Andy. So there's two things, I think, that I can say. We do have inventory for the old -- not the old, but the clinical material. So I don't see that as a problem. And that's an active CMC process. So when we manufacture doses in some jurisdictions, we use that process still today just because it's a very convenient scale of manufacturing for like clinical trial use.

So yes, the short answer is we do have inventory. I also want to reiterate a statement that I made earlier. We do have a clinical comparability study, not part of the original BLA submission. We did this study, frankly, because we wanted to be prepared for dossier submission in other jurisdictions. We have a centralized European submission planned, and we're negotiating a date for submission for that as part of our -- as you would expect, our global rollout of Zircaix.

And so drug development, as you know, doesn't stop the day you file your BLA. There's a continuous data gathering process, and we felt that there was merit in running additional studies, which we have done. So the FDA will have to opine on whether that additional clinical study that we have is something that's adequate.

We think it is. If not, if we need to throw a few more patients into it or we need to do a slightly expanded study, we can, a, do that very quickly. We have open comparability study protocol today running. We have an expanded access program that's running today, although the FDA will certainly opine in our Type A meeting whether or not that's something they'd want to keep going -- want us to keep going on.

They were very comfortable with us continuing the expanded access program with Pixclara. We'll have to see what they say about Zircaix. But I don't see any difficulty in getting additional patient data on top of the current patient comparability data that we already have. So yes, this is a really great question, but that's not going to be a rate-limiting issue for us.

The next question comes from John Hester from Bell Potter.

I was going to ask a question about the EAP, but you've just answered that, so thank you for that. Any downstream effect on the rest of the business, Chris, in terms of your R&D program? I mean this was hopefully going to generate a fair bit of cash in the next 1 to 2 years. Do you see any reason why you would need to pull back any other programs as a result of this outcome today?

Well, again, I don't want to be misleading, but I don't think we're talking about really material time delays. I mean, obviously, we'd all like to be -- I think all of our shareholders would love us to be seeing -- to be making more revenue streams. We have had a super intense year this year. I think it's fair to say -- and that comes from -- obviously, we're doing a product launch right now.

Our [ X ] code for Gozellix comes into effect 1st of October. So we're really gearing up for that. We've just announced our BiPASS Phase III trial that's launching. That's going to double the size of the market opportunity for PSMA. We've got European, I think, 20 -- nearly 20 European approvals or 19 European approvals. So we've got market launches going on there. So there's a fair bit of activity that can reinforce those revenue streams already.

And so I think it's not a catastrophic speed bump. From an R&D investment perspective, we're always looking at the sustainability of our R&D strategy. We'd ideally like to self-fund it as much as we can. But again, I don't think this is a -- this isn't a material issue for the company. Dave Stanton in his question kind of throughout the number of a year, I don't see this as being a year delay. I see it considerably less than that.

But again, we won't really know until we finalize the issues that the FDA has raised. But it's onward and upward. We're financed to take on ProstACT Global and the major clinical activities that are currently activated, and I'm pretty comfortable with that. I'll take one more question, and I think we're going to have to wrap it up because I actually need to catch an airplane, so I apologize for that. So fire away.

The last question comes from David Stanton from Jefferies.

I'll be very fast. I mean bottom line is, Chris, does this affect R&D spend for F '26? You probably answered it in the previous answer. I just want to check.

Yes. I mean we're trying to -- I think what we've said very consistently along the way is that our R&D spend will grow with our revenue stream. And we haven't forecasted yet what the impact of Zircaix is. Obviously, there's some fairly good models out there, including yours about where the product will go. So there's always a launch ramp-up time. We see the unmet need for Zircaix is really there. We'd ideally like to keep the momentum up for launch by maintaining the expanded access program.

Again, we'll have to have a conversation with the FDA about that. But I think really, this needs to be taken as a speed bump rather than a catastrophic event from an R&D investment perspective. Yes. Thanks for your question. Look, unfortunately, we'll have to wrap it up there, but I appreciate the questions and the candor of the questions. Just as a final parting comment, I started the company to take this product to market, and I'm personally disappointed in this delay.

That said, it really doesn't reflect the quality of the technology or the approvability of the product, and the team is really committed to getting it done. I also think that it is important to understand this isn't going to be the last product like this that we commercialize and the lessons learned are valuable.

So these CRLs, whilst they're frustrating, they certainly help us to become a better company, and we're learning a lot of things that are super relevant to the development of the whole portfolio. So I know that's not much of -- not much of a consolation, but the patience is appreciated. And thank you for your time today. I'll wrap it up there.

Thank you for standing by, and welcome to the Telix Half Quarter 2025 Results and Investor Webcast. [Operator Instructions]

I would now like to hand the conference over to Ms. Kyahn Williamson. Please go ahead.

Thank you and everybody, for joining us this morning and this evening for those joining from overseas. My name is Kyahn Williamson. I'm the SVP of Investor Relations and Corporate Communications at Telix. You can see there our disclaimer.

Just moving forward to Slide 4. I'd like to introduce today's speakers that are on the line with me. We have Chris Behrenbruch, our Group CEO and Managing Director; Darren Smith, our Group Chief Financial Officer; Kevin Richardson, CEO of Telix Precision Medicine; and Richard Valeix, CEO of Telix Therapeutics.

Today, we'll be taking you through the H1 2025 financial results presentation lodged earlier today on the ASX and our operational achievements for the half. This call is scheduled to run for 1 hour. And following the presentation, we'll take questions firstly from analysts on the phone and request that you ask one question at a time and hop back in the queue if you have further questions. If we do not get to your questions on the webcast, we will reply to you directly.

Moving on to Slide 5, please. In today's presentation, our business leaders will be talking to the investments we have made in the business to set it up for long-term value creation. This slide illustrates the scale of our business today, spanning development, commercialization and global production and manufacturing. It's been a rapid transformation.

This time last year, we had one approved product, Illuccix, which was commercial in just a handful of companies. Today, we have multiple approved products. We are preparing to roll out Illuccix across Europe and are preparing for launch of Zircaix and Pixclara. The acquisitions we have made have seen our manufacturing and distribution sites grow to 38 and our workforce has more than doubled with now over 1,000 employees globally.

Next slide, please. We've previously presented our growth strategy that is in place to drive value creation for the long term. You can see the 4 pillars on the left-hand side of the slide and the achievements we have delivered against each one this half.

These pillars are to grow our precision medicine or commercial stage imaging business and the achievements this half are focused on the goal to grow our share in the PSMA market and bring new products to patients. Kevin will discuss this further. Delivering on our late-stage therapeutics pipeline and building our next-generation pipeline, including alpha therapy candidates. This half, we have made solid progress across an array of programs, which Richard will take you through in more detail.

And finally, the expansion of our global delivery infrastructure, a key highlight this half has been the integration of the RLS business. Chris will take you through this and the key value drivers aligned to our strategy. Firstly, however, Darren will talk you through the financial results for H1 2025 in more detail.

So I'll hand over to you, Darren.

Thanks, Kyahn, and welcome, everyone. From a financial perspective, the first half of 2025 was characterized by strong commercial growth in our Precision Medicine business and continued investment into building our business for the future. We delivered strong revenue growth in the first half of 2025 with group revenues improving 63% year-on-year and driven by growth in Illuccix and the addition of third-party revenue from RLS.

Our precision medicine revenues were up 30% year-on-year with EBITDA improving 24%. Gross margins in our Precision Medicine business remained stable at 64%, reflecting efficient manufacturing of Illuccix. The group's gross margin was 53%, reflecting the addition of RLS third-party product mix and the associated manufacturing and distribution costs.

In this half, we have made a significant investment into our global manufacturing infrastructure to ensure that we are well positioned for long-term growth and we continue to invest in our R&D pipeline with investment up 47% year-on-year. Following these investments, we generated $18 million in operational cash flow and finished the half year with a healthy $207 million cash on hand.

Now moving to the next slide and our group revenues. Telix generated revenues of $390 million. This consisted of $79 million in revenues from RLS third-party sales and $311 million mainly from our Precision Medicine business. This represents an increase of 63% year-on-year and 41% compared to the second half of 2024. Illuccix continues to deliver strong growth, especially as it relates to volume doses. Kevin will provide more detail later in the presentation.

Now moving on to the next slide on the group P&L. As stated previously, the group P&L represents a period of solid growth and strategic investment into preparation for delivering future long-term growth. Group gross margin landed at 53% following the addition of RLS third-party products and RLS associated manufacturing and distribution expenditure.

R&D increased 47% to $82 million. As planned, we increased our investment into our therapeutic pipeline to be 54% of our overall investment in R&D from 43% last year. Richard will talk to our therapeutic portfolio later in the presentation. Selling and marketing expenses increased to 13% of revenue from 10% last year as we prepared for the product and geographic expansion of our Precision Medicine business and the addition of $7 million in selling and marketing expenses from RLS.

Manufacturing and distribution expenditure, excluding RLS COGS increased to 5% of revenue from 4% last year, driven by investment in our manufacturing and distribution infrastructure in ARTMS, Iso Therapeutics and multiple TMS facilities. General and administration expenses decreased to 12% of revenue from 16% of revenues last year. As a result, adjusted EBITDA declined to $21 million, driven by our investments.

Now moving on to the next slide. This slide represents the income statement of our Precision Medicine business. As you can see, gross margin is steady at 64%. This indicates that we have maintained our operational efficiency of Illuccix, enhancing our ability to reinvest in growth.

As planned, we prepared for new product launches and geographic expansion, increasing selling and marketing expenses to 12% of revenue, facilitating the build-out of our commercial infrastructure ahead of the expected revenue growth. This increase was offset by reductions in percentage of revenue spend on R&D and general and administration. As a result, the precision medicine EBITDA improved $20 million year-on-year, driven by 29% revenue growth.

Moving to the next slide of our TMS business. Moving on to the next slide. As we have made significant investments into TMS, I thought it was important to provide details, in particular, the contribution of RLS, which we are reporting for the first time.

RLS is the largest component of the TMS business, employing over 500 people across more than 30 locations, integrating last-mile delivery capabilities for Telix. In the next 5 months -- sorry, in the 5 months since acquisition, RLS EBITDA was close to breakeven. The addition of further volumes of Telix's products through RLS will improve the contribution.

RLS currently processes 1/3 of Telix's group revenue with total network revenues for the 5 months being $110 million. This includes $79 million of third-party products and $31 million of intersegment revenues related to Illuccix.

Gross margins for RLS were 7%, which is typical for this type of business and includes manufacturing and distribution costs from the radiopharmacies. RLS operating expenditure, excluding COGS for the 5 months since acquisition totaled $15 million. We expect these costs for the second half of 2025 to remain at a similar percentage of revenue.

Our TMS business also includes various subsidiaries such as Iso Therapeutics, ARTMS and TMS Brussels, Melbourne, Oklahoma, Sacramento, where we increased our investment to advance operational activities at each of these sites. Chris will expand on the TMS strategy later in the presentation.

Now moving on to the group's cash flow. In the first half of 2025, Telix has again achieved a positive operating cash flow totaling $18 million, demonstrating the ability of the commercial business to fund the development of our R&D pipeline and funding preparations for market and product expansion. As previously mentioned, Telix utilized cash on hand to make a number of strategic acquisitions. The largest of this was RLS. Cash on hand at the end of June was a healthy $207 million.

Now moving on to the next slide. I'd like to take a moment to go over our capital allocation priorities. Telix is focused on 4 areas: firstly, R&D development; secondly, optimizing our commercial performance; third, strategic growth opportunities through M&A; and fourth, supply chain resilience and production capacity. We believe these 4 areas of focus will enable us to deliver long-term growth.

Within R&D, we are advancing several late-stage clinical programs and we are optimizing our commercial infrastructure to advance our commercial assets and expand into new areas of focus and geography. In terms of M&A, we invested in 3 strategic assets in the first half of 2025. They were RLS Radiopharmacies, ImaginAb and a FAP candidate.

We continue to invest strategically into our manufacturing and supply chain infrastructure to preserve our competitive edge and to ensure we are in a position to scale efficiently as demand grows. We do all of this in a disciplined way by ensuring that we have a prudent cash buffer on our balance sheet.

Now moving to my final slide. As stated on this slide, we are reaffirming our full year revenue and R&D guidance. We expect our revenue from Illuccix and RLS to be in the range of $770 million to $800 million. Our R&D investments, we expect to fall in the range of 20% to 25% increase on last year.

Finally, I'd like to take the opportunity to reiterate our investment strategy. For the next 3 years, we will grow revenues by advancing assets from clinical development to commercialization, expanding indications and geographic expansion. We will reinvest the earnings into our portfolio and ensure that we have the capabilities, infrastructure and readiness to deliver on our therapeutic programs.

At this stage of our development, our priority is building long-term asset value rather than optimizing near-term EPS growth. We believe that focus on earnings too early can be troughed from the strategic investments needed to unlock the full potential of our pipeline.

I'll now hand you over to Chris Behrenbruch, Managing Director and Group CEO. Thank you.

Thanks very much, Darren, and good day to everybody online. So I'd like to start by taking a moment, if you could advance on to the next slide, please, to talk about why Telix is highly differentiated and built for long-term success.

Starting with our therapeutics pipeline. Our pipeline is built around areas of high unmet medical need with a diversified portfolio strategy that gives us multiple shots on goal, even in some cases, concentrated in the same disease area.

Our R&D efforts remain sharply focused on advancing next-generation assets, whether that's in the alpha or beta therapies, novel isotopes or innovative targeting agents. As a data-driven organization, our decisions are grounded in rigorous scientific and clinical evidence, ensuring that we prioritize our limited resources towards the most promising opportunities.

Turning to manufacturing and supply chain excellence. I want to emphasize that radiopharmaceutical manufacturing and distribution is an extremely complex business from an operational quality and regulatory perspective. A robust, reliable supply chain is critical to long-term success, especially for a multiproduct portfolio like ours that's also going to one day deliver therapeutic outcomes.

This is why we've made strategic investments in selective aspects of vertical integration over the past couple of years, alongside deepening relationships with key strategic partners that we think are best aligned with our long-term commercial strategy.

Our investment in commercial infrastructure is starting to deliver real operational and financial returns, including with continued volume growth for Illuccix in a maturing market landscape. This performance reflects our proven track record in commercial execution and I think it positions us very well for future product launches.

This year also marks a major inflection point for Telix as we transition from effectively a single product, single market company to a multiproduct, multi-region commercial organization. And we've done it pretty cost effectively. With this global infrastructure in place, our precision medicine assets are laying the operational and financial foundation for the rollout of our future therapeutic pipeline, which, as a reminder, is really not that far away.

Next slide, please. So within prostate cancer, our multiproduct strategy supported by next-generation follow-on assets is designed to drive sustained revenue growth. This approach strengthens our market position while expanding our commercial runway. We may have been second to market with Illuccix, but we are leading our new strategy through a life cycle management initiative that will enable us to continue to capture market share and to compete on the merits of our product portfolio to dramatically reduce the impact and viability of new entrants.

We'll continue to expand the market -- we'll continue to expand the market through new indications and indication expansion, notably our BiPASS study, a groundbreaking Phase III study that's aimed at expanding the label to use Illuccix and Gozellix right to the front of the patient journey with the potential to disrupt current diagnostic pathways and significantly expand the total addressable market. Kevin is going to talk more about this exciting near-term opportunity during his part of the presentation.

Finally, we continue to focus on product innovation, leveraging the strength of our distribution model, customer service and innovation focus to maximize product choice to the benefit of physicians and patients. For example, we recently unveiled the AlFluor chemistry program. This first application -- the first application is the development of a PSMA targeting agent that enables us to combine the imaging benefits of fluorine-18 with the convenience of gallium kit-based workflows the market has already come to appreciate.

We have an extensive clinical data package to support this, including a Phase III study in a significant number of patients. Following a helpful consultation with the FDA, we are now planning a registration-enabling study to take this forward to a new drug application.

Next slide, please. Let's take a moment to understand what transitioning from a single product, single market company to a multiproduct, multi-region commercial organization actually means. It takes a highly complex global manufacturing and distribution infrastructure to deliver our precision medicine assets and obviously, future therapeutics that are coming down the pathway to patients.

Due to the relatively short half-lives of isotopes and the need for just-in-time manufacturing, highly specialized facilities and logistics are required to avoid factors throughout the journey that can lead to disruption and delays. We have continued investing in our manufacturing infrastructure globally to have greater control throughout the process and significantly reduce quality and delivery risk. We see this as a crucial point of competitive advantage because without reliability, there is no commercial traction in this industry.

Our global footprint -- global footprint reflects our commitment to leadership in radiopharma. We believe a truly global presence is critical to becoming and maintaining market leadership in this space.

Next slide, please. On the topic of RLS integration, the RLS acquisition was a highly strategic investment, enhancing our U.S. presence, which is a critical market with a production and distribution network that covers over 85% of the U.S. and provides last-mile delivery and a footprint to expand our manufacturing capability in the U.S. Darren has already talked to the financial contribution of RLS. I want to touch on the value drivers and integration progress to date.

In just 5 short months, the integration is going very well, and I have been personally extensively involved in the process alongside Darren Patti, Telix's Group COO. RLS can deliver value in the following ways. Firstly, we are already seeing the synergies of having 2 distinct commercial teams that complement each other in terms of the way that they view and engage with the market.

Having a nuclear pharmacy network provides a new entry point and insights, bringing us closer to the customer and enabling us to identify significant new opportunities. To be clear, our team manages everything from producing the end dose, quality controlling it to walking it into the clinical site. This business is all about service to the end customer.

Second is a pathway to margin improvement. The volume of Illuccix sales through the RLS network has increased by 50% on a dose volume basis in the first 6 months since the acquisition. This is not at the expense of our key partners, rather it demonstrates the synergies between the 2 commercial organizations and our ability to capture commercial white space and optimize our competitiveness.

PET agents like Illuccix and Gozellix reflect higher-margin, higher-value products for nuclear pharmacies to distribute. As we increase product distribution of our own products through RLS, we expect to see long-term improvement in gross margins and the ability to mitigate competitive and distributor risk.

Finally, our goal with RLS is to build a radio metal production network to meet future demand for imaging and therapeutic radiopharmaceuticals to grow the RLS business, but also to reduce our own reliance on third parties for supply chain in the U.S. Again, with this investment, we will be focusing on high-margin products, not historical commoditized products.

We are currently in facilities planning and development for 6 cyclotrons across the RLS network initially with the facilities upgrade process to commence in the second half and will be complemented by in-house capabilities to produce select therapeutic products alongside our pharmacy production function for dose drawing and dispensing. So this will support both commercial activity and clinical activity.

Next slide, please. So the third part -- third pillar of value creation that I want to touch on is our therapeutics pipeline and platform. We are deeply committed to bringing our therapeutics to the market and this ambition remains a central focus of our investment strategy. As you heard from Darren, it's a growing proportion of our R&D expenditure. We are making meaningful progress across the entire pipeline and the momentum we're building reflects the strength of our execution. I'm going to let Richard speak more about our progress generally across the pipeline.

With the acquisition of Los Angeles-based ImaginAb, we acquired a biologics and drug development platform that's really well optimized for targeted alpha therapies. This is an incredibly talented team of people with a huge amount of experience backed by key opinion leaders that have a great vision for what the future targeting platform will look like in radiopharma. The acquired platform uses small engineered biologics or antibodies that enable highly specific cancer targeting combined with fast tumor uptake and blood clearance.

With our capabilities in antibody engineering, linker and chelator optimization and isotope selection, we're really well positioned to develop highly potent and targeted radiopharmaceuticals that range from small molecules all the way to advanced biotherapeutic products. We believe these specialist in-house R&D capabilities are fundamental for long-term success of the company.

So the next slide, please. So just to wrap up in terms of expectations around top line and bottom line growth and reiterating some of the messages that Darren has given you, I've been showing this chart in our investor presentation since the start of the year and there are some important signaling aspects to this graphic.

We are now in the middle stage of our trajectory where we're diversifying our revenue streams, expanding globally and derisking the business. If you recall, our midterm strategy has been to reinvest our revenues into the business to fuel long-term growth. We're making very targeted investments today to position the company for long-term growth, both in top line expansion and bottom line performance. But right now, it's without putting every last dollar into that growth and infrastructure that when we hit our pre-commercial launch year for the Therapeutics business, we are really ready to go.

I want to give a little final comment before I hand over to Kevin and take a moment to address the information request from the SEC. I know many people have had questions about it. I'm personally disappointed to be in the situation as I really don't believe it reflects the quality of our organization or our commitment to excellence.

The subpoena was a request for documents primarily relating to our disclosure activity related to the development of our prostate cancer therapeutic candidates. We are in the process of responding to the SEC to resolve this as soon as possible. I want to make clear that there have been no allegations or charges leveled at the company or any individuals. We do not know what or who triggered this.

Let me be clear, this has no impact on our commercial portfolio or the momentum of our pipeline development. In fact, we're operating with more urgency and focus than ever before to bring these breakthrough assets to patients. I believe you can see evidence of this progress in today's presentation.

So with that, I'd like to transition over to Kevin, our CEO of Precision Medicine for a commercial update. Thanks, Kevin.

Sure. Thank you, Chris. And for my first slide, I would like to start with our precision medicine growth strategy. Our growth strategy is based on 3 pillars: expand product offerings, expand geographies and then expand indications on those products.

In terms of our first pillar, expanding our product offerings, we have now launched Gozellix, further strengthening our position in the PSMA space. And looking ahead, we have 2 near-term regulatory milestones with Zircaix and Pixclara. These assets will build on our strong commercial foundation established by Illuccix.

Moving on to our second pillar. The global rollout of Illuccix continues to progress well with marketing authorizations now secured in over 23 countries. Turning to our third strategic pillar. We are actively exploring new indications for our existing assets, particularly indications where we believe we can deliver meaningful impact for patients. We remain laser-focused on the execution of these 3 strategic pillars, driving the expansion of our global Precision Medicine business and paving the road for our Therapeutics business.

Next slide, please. Illuccix continues to deliver strong growth in the high single digits. In the second quarter, Illuccix revenues were up 2% quarter-over-quarter or 25% year-over-year with dose volumes up 7%. Q2 represents the highest unit volume growth we've seen in the last 5 quarters. And despite competitive pricing pressures, we continue to manage the impact to our average selling price. To do so, we continue to drive share growth in clinical accuracy and reliability of dose delivery.

Our clinical message is Telix PSMA gallium agents have fewer indeterminate bone lesions and higher inter-reader agreement than F-18 assets. We couple the clinical message with a highly specialized sales force and customer-facing teams that differentiate Telix with our customers every day. We've developed a reputation in the marketplace as an innovator, paving the way for successful launch of our follow-on products.

Next slide, please. Moving on to geographic expansion and the global rollout of Illuccix. As you can see, we've established a strong commercial footprint across key markets, including the U.S., Canada, Australia, Brazil, the U.K. and Europe with marketing authorizations now secured in 23 countries.

In the second quarter, we successfully launched Illuccix in the U.K. and see encouraging uptake. In the next wave of launches, we are focused on key markets like France, Germany, Italy and Spain. And as you move further east, we're focused on China and Japan, where in China, we have completed our registration study and are preparing an NDA for Illuccix. While in Japan, we are just initiating our Phase III study for Illuccix, and we are happy with the progress thus far.

Now on to Latin America, where we have the first approved product for PSMA PET and we have commenced commercial operations there with our partner on the ground. Overall, we remain on track with the global rollout of Illuccix, supported by strong execution in the U.S.

Next slide, please. We launched Gozellix earlier this year and successfully delivered our first commercial doses in June. The launch is progressing well through our comprehensive network of distribution partners, Cardinal Health, Pharmalogic, Jubilant and RLS.

Telix is the first company to bring 2 PSMA-targeted agents to the market, a differentiated strategy that we believe is central to our competitive advantage. This dual product approach gives customers meaningful choice, whether in terms of economic value or scheduling flexibility and it reinforces our commitment to meeting diverse clinical and operational needs.

Now from a reimbursement point of view, we are pleased with the recent HCPCS code we received from CMS, a major reimbursement milestone and look forward to getting an update on the decision around transitional pass-through status in the near future. The HCPCS code will be effective October 1, 2025, streamlining the billing and reimbursement in the hospital outpatient setting for Medicare-eligible patients.

Next slide, please. Moving on to our third pillar of growth strategy, label expansion. I wanted to talk about a study that we think has the potential to become the future of prostate cancer diagnosis, our BiPASS biopsy study or biopsy of the prostate avoidance stratification study. Biopsy are highly invasive and carry risk and there are more than 1 million patients getting a biopsy every year with up to 75% of them being negative.

When you think about it, what it takes to really be disruptive in this space and be innovative, we think it's minimizing patient trauma, reducing risk and recovery time and lowering cost while improving patient outcomes.

Next slide, please. BiPASS is the first registrational study combining MRI and PSMA PET in diagnosing prostate cancer. Patients are categorized into high, medium and low-risk categories for prostate cancer. And for high-risk category, an image-guided biopsy would be recommended. For the intermediate or an indeterminate category, a precision biopsy would be recommended since PSMA is much more sensitive in the detection of prostate cancer and we can perform one and done.

For the low-risk category, if there is no uptake of PSMA in the scan, we can conclude that no biopsy is needed, none and done. So with this study, we aim to improve the predictive accuracy of prostate cancer while reducing the number of biopsies. This study has the potential to significantly broaden our market opportunity, potentially doubling it. We see significant value in moving earlier in the care pathway by positioning our scan at the front of the patient journey.

Next slide, please. Moving on to Pixclara. We've engaged with the FDA and agreed on a pathway forward and plan to resubmit the NDA. Recall that the FDA has granted Pixclara Orphan Drug and Fast Track designation, an acknowledgment of the drug candidate's importance in addressing a significant unmet medical need.

Turning to Zircaix. Our PDUFA date is approaching next week. We view this as a transformative opportunity targeting an area with no approved therapies. If approved, Zircaix will be first to market, positioning us to lead in the space with significant unmet need for patients and commercial potential.

So to summarize, we've built a robust commercial infrastructure that continues to deliver, highlighted by high single-digit growth for Illuccix in the U.S. We've secured marketing authorizations in 23 countries and successfully launched in the U.K. Gozellix, our next-generation PSMA agent, is now on the market with HCPCS reimbursement starting in October. Looking ahead, we have several near-term regulatory milestones, and then we believe our BiPASS study has the potential to redefine the diagnostic pathway in prostate cancer.

So with that, I'd like to introduce you to Richard, who will provide you an overview of the therapeutic assets.

Thank you, Kevin. So let me present to you today the update of our Therapeutic business unit. And you will see that during the first half of this year, 2025, we were moving the needle on all our therapeutic areas. You can see on this slide, our strategic focus is centered around 3 therapeutic pillars: first, urology oncology; second, neurology oncology; and third, solid tumors and hematology.

So within urology, we have a pipeline asset for prostate cancer and more specifically targeting the mCRPC standing for metastatic castrate-resistant prostate cancer. And also kidney cancer, we're targeting the ccRCC indication for clear cell renal cell carcinoma. But we have also a therapeutic agent such as TLX090 for metastatic bone pain deviation, which is frequent in the prostate cancer late stage.

Within neuro-oncology, we have a pipeline asset for glioblastoma. And I'm happy to share that we are also adding a new indication for leptomeningeal disease with the alpha version of the TLX102 compound. Within our third pillar regarding solid tumors and hematology, we have the TLX400, our FAP-targeting asset that we closed the acquisition during the Q1 2025. This asset has the pan-cancer potential and we are exploring various indications. We also have molecules for soft tissue sarcoma and bone marrow conditioning agent for pediatric high-risk leukemia patients. I will come back on that in a minute.

In summary, you can see that we have 10 early and late-stage assets. Late-stage assets, primarily focused on beta therapies, followed by earlier-stage assets exploring alpha therapies. In addition to these 10 assets, we also have preclinical compounds targeting for the most well-known DLL3 and alpha v beta 6 coming from the ImaginAb acquisitions. We are exploring the best combination with isotopes for these targets.

Our diagnostic strategy includes having a companion diagnostic for all our disease area of focus, and we are working in close collaboration with Kevin and the precision medicine colleagues.

Next slide, please. Let's talk about prostate as the first pillar of our urology strategy. TLX591 is our Phase III asset for mCRPC. And let me remind you that ProstACT GLOBAL is a combination trial with standard of care, namely we are associating the product with abiraterone, enzalutamide and docetaxel with 10 patients in each arm. This is a 2-part study where the primary readout from the Part 1 will be safety and dosimetry. And I'm pleased to disclose that we have reached target enrollment of 30 patients in the Part 1 and we'll provide an update once the data analysis is complete.

Part 2 of the study is a randomized treatment expansion, including 490 patients. In order to accelerate ProstACT GLOBAL Part 2, firstly, we are currently in the process of getting the required regulatory approvals in various countries in order to expand the number of sites. Secondly, the protocol in Part 2 is more patient friendly in that the patients will not need to come back to the hospital for multiple scans, which were required in the Part 1 to complete the dosimetry data.

Let's move on to TLX592, which is our next-generation PSMA targeting alpha therapy using actinium in development. Earlier this year, we presented data at ASCO GU from our clinical study evaluating the biodistribution and the dose to the organs of the copper-64 level imaging version. This was essentially a proof of concept of this asset and we are really looking forward to moving into Phase I. I'm pleased to say that we have now received the Human Research Ethics Committee approval in Australia for first-in-human study with this 592 asset.

Let's move forward, TLX090, our Samarium agent. This is being developed to treat the pain palliation in patients that have osteoblastic metastatic disease. It fits nicely and perfectly with our urologic platform because frequently, the patients that have osteoblastic metastatic disease have prostate cancer.

Currently, we are developing this as a single-dose agent for pain palliation, but there is potential in the future for multiple dose regimens as well. And I'm pleased to announce that we just received the FDA approval for Phase I study and look forward to start. It's another great milestone for this first half of the year 2025. I'm sure you can agree with me.

Moving to the next slide. Our second pillar of the urology strategy is focused on kidney cancer. TLX250 is our CA9 targeting agent. We know that CA9 is expressed in greater than 90% of clear cell renal cell carcinoma. It's also being expressed in a number of solid tumors. We have a few ongoing studies exploring mono and combination therapy.

We are focusing on monotherapy for advanced third and fourth-line patients with ccRCC. And I'm pleased to announce again that we are moving forward a pivotal trial named LUTEON with the submission completed to the Human Research Ethics Committee in Australia. On the right-hand side, you can see images. This is a patient with metastatic advanced renal cell carcinoma. On the top, you can see the initial images that have been performed with zirconium level girentuximab scan.

You can see intense activity in the sacrum where there was a metastatic lesion. And after 3 cycles of therapy with lutetium girentuximab, you can see on the bottom row that the amount of activity in the sacral lesion has significantly decreased, again, giving us confidence that the injected therapy has made its way to the bone lesion.

Now if we consider the life cycle of girentuximab compound, let's have a look to the TLX252, our CA9-targeting alpha therapy for pan-tumor approach, including ccRCC. When patients have high expression of CA9, they often face resistance to chemotherapy, immunotherapy and with time also radiotherapy.

We think this is a good target for radioligand therapy because with an alpha isotope, we can use the increased activity directly targeting the tumor cells. We have submitted to the Human Research Ethics Committee application in Australia in late Q2 and look forward to start our Phase I trial once we receive ethics approval.

Let's move to the next slide and moving to the neuro-oncology portfolio. I will start with the good news of receiving full ethics approval in Australia to start the IPAX-BrIGHT. IPAX-BrIGHT is a pivotal registration-enabling study in recurrent glioblastoma. Given the absence of effective options for glioblastoma, we are very pleased that this agent has been granted an Orphan Drug designation, both in U.S. and Europe for treatment of glioma.

Our initial focus with PDX101 is going to be in glioblastoma, the most common and aggressive form of primary brain cancer. There is no established second-line treatment at this point. And if we look at the NCCN guidelines in U.S., it tells you that the clinical trial [indiscernible] is option for treating second-line patients with recurrent disease.

Also, I just wanted to summarize data that we disclosed previously this year. IPAX-1 and IPAX-Linz in the recurrent setting demonstrated an acceptable safety profile as well as encouraging overall survival duration, both from the time of recurrent diagnosis ranging from 12 to 13 months and time from initiation of treatment from 23 to 32 months. It's a great achievement when we know the average life expectation, which is extremely reduced in this debilitating disease.

On the right part of the slide, you can see a patient case coming from a compassionate use program in Europe. In this patient, the scans describe a stable disease for 18 months, very encouraging when you know the severity of this disease.

Turning to our targeted alpha therapy approach in neuro-oncology, utilizing astatine isotope. We believe patients with smaller, more diffuse disease may be well suited with the mechanism of action and the higher energy deposition of astatine-211. We are currently in the process of preparing regulatory filing for submission for leptomeningeal disease and conducting a collaborative initiated -- investigator-initiated trial in glioblastoma.

Let's move to the next slide, please. And focusing on the other solid tumors and hematology disease. Let's start with the TLX400, our FAPi, which stands for fibroblast activation protein inhibitor, an antigen expressed on the tumor microenvironment. The diagnostic piece has been confirmed in patients and we have several publications on the topic. We are looking forward to bringing this molecule to the clinic.

The Phase I pan-cancer Basket study starting -- will start in 2026. The other 2 molecules we have are TLX300 in licenses from Lilly, PDGFR alpha for advanced metastatic soft tissue sarcoma. We have initiated a Phase I ZOLAR imaging trial that is recruiting patients in New Zealand and Australia. We also have the TLX66 for bone marrow conditioning for allogeneic stem cell transplantation, more specifically in myelodysplastic syndrome and acute myeloid leukemia. Let's move to the next slide.

In conclusion, it is an extremely busy first part of the year. Telix has one of the most complete therapeutic portfolio with 10 pipeline assets and even a few more if I add some the research stage with ImaginAb recent acquisition. Within urology and neuro-oncology, we are progressing, initiating 3 pivotal trials.

First, advancing the pivotal trial with ProstACT GLOBAL; second, preparing the pivotal trial LUTEON for the 250 compound and starting the pivotal trial IPAX-BrIGHT. We are also starting the clinical trial with the TLX090, which is the perfect companion product for our ProstACT portfolio. And I don't forget that we are entering first-in-human trials with our 2 alpha emitters, TLX592 and TLX252.

Thank you for your attention.

Thanks very much, Richard. Great rundown and really conveys the depth of the pipeline and development activity and progress over the last 6 months. So as is typical, I get to end the presentation with a summary of our upcoming catalysts and key objectives. This is by no means an exhaustive list but captures some of the key value creation events that are on the near-term horizon. Many of these catalysts are new commercial opportunities that will add to our revenue and earnings growth and will support our expansion and transition into a fully-fledged theranostics company.

Some of these catalysts relate to new clinical data points that I believe will reinforce our leadership position as an innovative player in the radiopharma space with pipeline of either best-in-class or first-in-class assets. Expanding our capabilities is a key driver of near-term value creation as we work to deliver our products into major global markets. Our investments are focused on building the operational strength needed to unlock these markets and then, of course, to scale sustainably.

In closing, Telix continues to demonstrate strong growth and operational improvement. We've never been more focused or committed to delivering value for our shareholders, our clinical partners and most importantly, the patients we serve.

Thank you for your attention. I hope you found this presentation interesting and informative, and I now open it up for questions.

[Operator Instructions] Today's first question comes from David Low with JPMorgan.

If we could start with just the outlook for gross margins. I mean I think it was very useful to get all the update on RMS (sic) [ RLS ] and understand exactly where the contribution is, but I heard the message that you think it can improve. And then, of course, we've seen some fairly significant changes in PSMA pricing in the last quarter, particularly the back end. I'm just wondering how that's going to play out and of course, trying to understand how Gozellix fits into that mix as well. So if I could have someone have a go at answering some of those facets, please.

Well, Darren, why don't you -- it sounds like 3 questions, not one, but why don't you go ahead, Darren, and start off with the gross margin.

Yes, sure. Thanks, David. Obviously, this half year has been quite a change for the organization where we've compared to the prior year where we're only selling Illuccix. And I think the first key point is that the Illuccix gross margin is -- and you can see this by looking at that precision medicine slide has remained fairly consistent. I think we reported 65% last year and 64% this year. So obviously, no real change in the gross margin perspective for Illuccix in the market from the gross margin.

Then when we look at RLS, we see there the addition of those third-party products and also the kind of internal contribution that it received by selling our Illuccix product into the market that they're able to achieve a 7% gross margin once you've included the radiopharmaceutical -- sorry, the radiopharmacy cost into the cost of goods.

The interesting thing we have done a little bit of benchmarking and what we found is the industry that's similar, some of our partners/competitors are doing a very similar gross margin in that kind of low to mid-range single-digit yield. So gross margin is obviously a result of those 2 businesses brought together. So the 53% is the average based on the load of business.

I think the important thing to remember, though, with RLS is that as we start to push a product like Illuccix and the higher contribution that it provides to the RLS business that, that should help grow the dollar gross margin for that business with little or minimal cost impact on being able to deliver that to patients. So what we would potentially see is as we add the more Illuccix and potentially the future products that we're looking to bring to market in Gozellix, Pixclara and Zircaix, that will continue to assist that business to make a better contribution to the organization. Hopefully, that kind of answers your question, David.

Yes. I think I don't have anything to add except for that, obviously, we didn't acquire RLS for its commodity radiopharmaceutical business. We acquired it to put a larger proportion of our own products through and to prepare for when we have to distribute therapeutic unit doses, which you can't do that without a nuclear pharmacy dose dispensing. If you want to deliver a prefilled syringe to a customer, which is the name of the game, you got to have a pharmacy network to do that. So this is not about like what's going to happen this quarter. It is what's going to happen in the next quarter and the quarter after that and 3 years from now. So let's move on to the next question.

The next question comes from Tara Bancroft with TD Cowen.

This is Nick on for Tara. I have one on the guidance and the continued growth of Illuccix moving forward. So to reach the 2025 guidance with assuming stable RLS revenue, obviously, it's a little bit difficult to say that right now. But it appears like Illuccix sales growth may be slowing a little bit. Is this due to the loss of pass-through status? And what impact could this have on Illuccix net sales? Also, could Gozellix need to return to growth once it does have pass-through status?

Yes. I mean, obviously, we give guidance on an annualized basis, not on a quarter-by-quarter blow. So you're absolutely correct. 1st of July, we came off pass-through. We actually reported 7% growth quarter-on-quarter, which is, I think, exceptional -- 7% growth in volume quarter-on-quarter, which is really exceptional performance if you -- particularly if you take some of our competitors' financial results into consideration.

So what we did is we made a decision that we were going to stabilize our customer book going into the third quarter. We have the situation where we have one product coming off pass-through and then another product getting reimbursement effective 1st of October. And we've got to bridge that gap and we chose to take certain commercial actions to do that. And we still had growth in revenue quarter-on-quarter, again, where our competition didn't. And so I think we have a nice stabilization strategy for Q3 and then Q4 continues with the advantage that we uniquely have of a second product introduction.

I don't know, Kevin, if you want to add anything to that?

I would just add that we just continue to take the market pragmatically and continue to sell clinically on our accuracy as we spoke of earlier in my presentation and then continue to drive that message with reliability. And again, we have a strategic pillar and our customer-facing team that really represents well and is able to really manage that ASP and volume mix that we work on with that piece of the business and the strategic accounts.

Yes. And I think you'd be mistaken in thinking that this is just a pricing game. It's not. I think there's 4 pieces to commercial success in the market dynamic today, as Kevin said, selling on clinical value proposition, which we have demonstrably the strongest clinical value proposition. It's selling on service and service quality. Then there is, of course, pricing and pricing structure, particularly for large volume customers.

Unlike our competition, we don't throw it all at the same price to everybody. We give benefits to our customers that are more loyal than smaller customers. And I think the last thing is clearly reimbursement status. And again, to reiterate, we go into Q4 with a very strong and differentiated commercial strategy with Gozellix. And we're excited about that. We're looking forward to it. Sales team is pumped.

Our next question comes from David Dai with UBS.

Congrats on the quarter. I'm just curious about the Zircaix launch readiness. Maybe you can highlight some of the things you've been doing for Zircaix and how should we think about the launch in the first and the second quarter after approval on August 27?

There's probably not too much to really kind of openly discuss. I mean the commercial team, it's not their first rodeo. We're selling into the same customer base, same referral physician base as Illuccix. So it's a very straightforward pathway to the customer. We're clearly focused on using our Illuccix customer base to seed that product launch. And I would say commercial team is ready to rock and roll on Zircaix. I don't know if you want to add anything to that, Kev?

No, I think the combination of a urological call point with a nuclear med physician base that's reading that is really the key to success there. And we've had an expanded access program going for a while that's demonstrated exactly what we saw in the ZIRCON study. So we're excited about the launch and just haven't given guidance for 2026 yet.

Yes. I mean we've had a lot -- the expanded access program, the EAP has been a huge success. We've done a very, I think, well-orchestrated unbranded physician education campaign. So as far as we're concerned, the market is ready for this product.

The next question is from Andy Hsieh with William Blair.

Congratulations on the performance. So for the BiPASS study, obviously, very provocative in terms of the disruptive potential. I'm curious, the trial is posted on ClinicalTrials.gov. You have some primary endpoints. Just curious about some secondary endpoints that you're contemplating on and how you think about some of the outcomes, longer-term outcomes for patients pertaining to survival or treatment steps that you can really, really convey the value of taking this agent upfront?

Yes. So this study was really born out of and driven by KOL engagement around where is PSMA going to really go as we move up the treatment cascade. And to be quite honest with you, on the front line of patient management, not a lot has really changed in the last sort of 15 years. It's pretty archaic. And whilst MRI, of course, gets better and better, we're still doing well over 1 million biopsies a year and a good proportion of those biopsies aren't adding any value to the patient journey.

So just to be clear, our goal is not to eliminate biopsy. I mean that's a nonsensical clinical objective. A biopsy is super important. What our goal is, is to make biopsy count and to use it where it's absolutely essential and to use the scope of biopsy where it absolutely makes sense to do that. In terms of the -- we will, of course, be putting out the trial design on ClinicalTrials.gov. It's only just -- that study is just launching. So clearly, we want everybody to understand the endpoints.

But to the implied part of your question, yes, there will be a monitoring period. It won't be a very long monitoring period, but there's definitely a follow-up period that's part of the evaluation of the utility of prostate imaging in that patient segment. So stay tuned, Andy, we've got more updates on that trial design coming down the pathway.

The next question comes from David Nierengarten with Wedbush Securities.

I just had one on the ProstACT study. Just around the parameters, you've recruited the patients. Kind of what are you looking for on the dosimetry and safety side? And when you think about the movement into the Part 2 of the study, is it still the plan to carry forward all 3 combinations? Or could that change in the future when you talk about the results from these first 30 patients?

Well, things can always change based on data. But we -- at present, our plan remains as stated. The real purpose of the Part 1 study and frankly, the reason why it took a while to accrue is because it's a multi-time point specto dosimetry, a lot of patient visits involved, typically requires specialist centers. So it's really a subset of departments that are really suitable for running that study. And it is, as I said, it's a demanding study on patients.

We know that when we move into the second part of the study, which in some countries is a seamless transition. So that's already in play. It's a very straightforward transition and a much more straightforward study protocol from a patient perspective. And the 3 different arms were because we had the aspiration in this study to have flexibility on the choice of RP. We think that, that's an important thing.

And so really, what we're looking to get out of Part 1 is confirmation of our understanding of the safety profile in combination with both RPs, different RPs and Taxanes. We fully expect that, that's what's going to progress into the second part of the study. We think that there's a compelling clinical use case for all 3 of those combos and our mission is to really demonstrate to the agency that, that safety profile is consistent across -- really across different RPs.

So I hope that answers your question, but we're really excited to have that first run-in part done. It was a pretty painful study protocol. The rest of the study now is going to pick up at a much greater pace.

The next question comes from John Hester with Bell Potter.

I want to just come back to the situation with PSMA pricing. I'm sure everyone on the call heard the comments from Lantheus a few weeks ago regarding the competitive situation and also Kevin referred to competitive pricing pressures in the market in his prepared comments. So the question is this, are you worried about that pricing pressure contagion spreading to your own market? And can you also sort of update perhaps on what you've seen on those pricing pressures in this current quarter?

Well, I think we've reported all the numbers. So the numbers are the numbers. I think that pricing is a direct function of both competitive dynamics and clearly, reimbursement status. The market is complicated. As you know, there are multiple customer segments in the market that have different competitive dynamics and different pricing dynamics.

What we do know is that customers prefer understandably to use a reimbursed product. Lantheus came off reimbursement, and that certainly puts pressure on their business. We've now come off reimbursement, albeit for a very transient period of time because we have been granted a HCPCS code for our life cycle management product. which, by the way, has innovative aspects in its own right. Like it's not just a direct follow-on.

There's some genuine clinical and clinical workflow benefits that comes from that product. So the way that we manage pricing and pricing consistency is by ongoing innovation and capability delivery to our customers and differentiating ourselves in that -- in both the clinical use case for the product and the reimbursement profile of the product. And so -- and I don't want to sound facetious, but no, pricing pressure is not what we worry about because we have a life cycle management strategy to address it.

Today's last question will come from Andy Hsieh with William Blair.

So Chris, I'm just curious if you can comment a little bit more about the aluminum fluorine technology that you mentioned that kind of allows you to traverse between the gallium-68 and fluorine-18 isotopes. Can you speak to maybe the commercial implication, i.e., what is the next steps in terms of potential regulatory pathway and then supply chain, how does that kind of fit into your goal of being a vertically integrated company, leveraging the RLS and ARTMS platforms?

Well, on the node, so I'll start off with the science lesson, and then I'll hand it over to Kevin to talk about the commercial implications and the physician preference. But essentially, when you react aluminum and fluorine together, it's pretty violent coupling. And what you end up with is a metallized version of F-18. And it turns out that, that metallized version of F-18 is a drop-in replacement for gallium.

So what it means is that you have the same targeting agent with the same chelator and you can interchangeably substitute either gallium or F-18. And the beautiful thing about aluminum fluoride is that you make it in extremely large quantities at a cyclotron facility. It's not a drug per se. It's essentially an API, a hot API.

And you can drop that activity then into nuclear pharmacy and using all of the benefits and the production workflow advantages that we have of the kit-based approach we can essentially, particularly in high-density areas or where we want to service large academic customers that really are enamored by F-18, and I'll get Kevin to characterize the customer base a bit more, but it enables us to seamlessly transition between gallium and F-18 and of course, continue that life cycle management.

And PSMA-11is really well demonstrated in terms of its sensitivity and specificity as a targeting agent. And now we get to marry that kind of superior pharmacology of PSMA-11 with the utility of F-18. And still, by the way, utilizing our well-trodden and well-understood distribution model. Maybe, Kevin, you want to comment on physician preference?

Sure. So as you know, we launched Illuccix 3 years ago and we've successfully taken over 1/3 of the market, pushing 40% of the market with gallium. And we believe that gallium is a fantastic product and we're going to continue to execute on our Illuccix and our Gozellix plan through the marketplace. But what we do see is some stalwarts that have used F-18 for many other products through the years and tend to favor that more.

The reality is that we believe our reliability story, along with our commercial customer-facing team can support that in the next couple of years as we move from -- in our life cycle management from Gozellix and continue to maximize gallium cells and then find, if you will, the corners of the canvas, if you will, to paint with AlF, and we believe that's a great product to do it through our distribution and commercial network.

Yes. So maybe just to wrap up because it's a super great question. And by the way, you're the first analyst that's ever asked a question about it. So that's why I'm grateful to elaborate a bit more. But going forward, I think what you're going to really see is we have a whole pile of imaging products coming down the pike, including, for example, there's a gallium FAP agent there.

As we develop that agent, we'll think about how this time do we avoid having to participate in a physician preference discussion, right? Some folks like gallium, some folks like F-18. Some guys drive the beamer, some guys drive the Mercedes. And we're going to set up shops so we can make both available depending on what the preference is.

All right. Well, look, I think Yes, I think we're at the end of time anyway. Well, thanks -- I just want to say thanks very much to everybody for your time today and I appreciate the opportunity to give you an update. Thanks very much.

That does conclude our conference for today. Thank you for participating. You may now disconnect your lines.

[Technical Difficulty] quickly built an integrated radiopharmaceutical ecosystem. We have a specialist commercial organization and a deep pipeline. The breadth and depth of this company we built is really differentiating us in this fast-growing industry. So today, we want to focus on just some of the key growth opportunities that are ahead of us.

A great place to have in the room, a selection of leadership at Telix. I will just run through those [Technical Difficulty]. So welcoming Dr. Chris Behrenbruch, our Managing Director and Group CEO; David Cade, our Group Chief Medical Officer, who's travelled here from Sydney; Richard Valeix, the CEO of our Therapeutics business; Kevin Richardson, CEO of our Precision Medicine business. And I would just like to call out in a little more detail, 3 members of the team who investors would not have met before. The first is Dr. Paul Schaffer, the Chief Technology Officer. He is in a newly created role, which commenced in April, but Paul joined us from ARTMS. He is a highly respected expert in this field, and then he leads -- led the development of the ARTMS QIS system. So he is really here to talk about some of our new R&D capabilities.

Alongside Dr. David Cade is the group Chief Medical Officer, and we have now added Chief Medical Officers based in the U.S. for our Therapeutics and our Precision Medicine business. Dr. Pamela Habib, who is our Chief Medical Officer for our Therapeutics business, is a trained breast radiologist, trained at Harvard, practiced for over a decade. From clinical practice, she moved into consulting with McKinsey & Co, where she advised hospitals, insurance companies and pharmaceutical companies on their growth strategy, and she's joined us from Bayer, where she held roles in Commercial Development, Medical Affairs and Clinical Development.

I'd also like to welcome Dr. David Liu. He is our Chief Medical Officer for the Precision Medicine business. David is a Professor of Radiology and Associate Professor, School of Biomedical Engineering University of British Columbia. He brings extensive medical practice experiences in interventional and diagnostic radiologists specializing in cancer therapy. His highlights include over 100 publications in peer-reviewed journals and involvement in the United Nations World Health Organization Blue Panel Commission, the cancer imaging, as well as developing international standards for cancer imaging in China, U.S., Canada and throughout Europe.

I'm also very pleased to introduce 3 esteemed KOLs in the -- physicians in the room, and we really do appreciate them taking the time out of their busy schedules to speak with you today. Our speakers will introduce them in more detail. But just to acknowledge that we have Dr. Joseph Osborne in the room, Professor Oliver Sartor and Professor John de Groot, who will speak about our kidney cancer imaging programs, 591 prostate cancer therapy and TLX101 therapy programs, respectively.

We do have a lot to get to today, so we will build in opportunities for Q&A at certain intervals, so we do ask that you hold your questions until then. As the event is being webcast, but we will prioritize questions for those in the room. But for those in the webcast, who have questions, send them through, and we will respond to you separately if we don't get to those today.

So with those bits of housekeeping, I'm going to hand over now to Chris.

Well, thanks very much, Ky, for the opening comments, and welcome everybody this morning. We're really appreciative of your time. This is an opportunity not just for us to give you an update, but really for you to get some Q&A out and to interact with the company. I think that's what makes the in-person meeting so effective. Can I just have the slides on the full screen just so I can -- my aging sight can -- I can see what I'm talking about.

So I think most of you know the company, although there are a few newbies in the room, and there's a growing kind of understanding of the business. I think it's starting to be understood that we are one of the leading companies in this space. And I think we have a very differentiated strategy, which is really summarized in this slide.

It's useful to think of TLX through 3 pillars of activity. First of all, we are a commercial stage pharma company with 2 approved products in the United States and a pipeline that's coming in behind that. We anchored our commercial activity in prostate cancer imaging, but we really have a bright future in many other disease areas with a particular depth of focus in urologic oncology.

You're going to hear today from my colleagues in medical and commercial side about the status of our Therapeutics program. We have -- alongside our portfolio in Precision Medicine, we have a really deep pipeline of molecules on the therapy side from things that are preclinical all the way up to Phase III. And so we'll be diving into most of the sort of later-stage programs to the clinical-stage programs during our session together today.

And then last of all, I think something that's quite differentiated and different about Telix, about 5 years ago, we started a program of really looking carefully at manufacturing supply chain. I think most people that are interested in radiopharma understand this is a just-in-time manufacturing environment. We have very short shelf-life products. To put that in perspective, when Illuccix goes hot, we have 2 hours to get it to patients and get it into patients. So it really is a logistically complicated business. And so you have to, to some extent own your manufacturing and supply chain. And I think we've done a really good job in the major markets that we serve of making sure that's an integral part of our operational excellence.

This would be your Telix strategy on a page. So today, you're going to hear about how we are delivering on our late-stage pipeline. I think we've had a lot of growth and evolution as a company in terms of how our Therapeutics team has developed and is executing clinically. We've made a number of acquisitions and internal growth projects recently that are around that next generation of our radiopharmaceutical products. These are things in the 5- to 7-year timeline for Telix. But in that context, we're thinking about particularly those next-generation isotopes and particularly alpha emitters.

Kevin Richardson, who leads our Precision Medicine business, is going to talk to you about some of the key commercial strategies behind our spectacular growth, and hopefully, future ongoing growth in our Precision Medicine business. There's a long way to go in prostate cancer. And then, when we think about urologic oncology as a key stakeholder in the near future, we see a lot of opportunities to build depth and breadth in that pipeline. And then last of all, as I've said, to make sure that every single day that we deliver that dose to a patient with the reliability and quality that's expected of a leading company in this space.

I'm not going to go through this, this is a repackaging in some respect from a sort of an operational and differentiation perspective. But I think there's 2 things that I would like to call out in particular on this slide. I think the first one is that commitment to a theranostic strategy. And there's a lot of companies out there that are more imaging focused. And I just want to be clear, we're not a diagnostic imaging company. We've made early revenue and early commercial foray as an imaging company, but that's because the pathway to market and the regulatory pathway is a lot more straightforward in some respects, still a sterile radioactive injectable. But I suppose in some regards, it is an easier pathway, but it's enabled us to be in the unique position where we can self-finance our growth in the main.

And -- but I think from a clinical perspective, what you're going to see today is the symmetry around the targets that we pursue, that for every target we go after therapeutically, we also develop an imaging agent. And we believe that, that delivers something important to the clinician. We think it derisks clinical trials. We think it helps to validate targets. I think one of the reasons why we have developed an enormous amount of clinical confidence around treating patients with PSMA therapeutics is because we know how good the imaging is, and we know how good the target is. And that really invites exploration into earlier lines of therapy because we understand the target so well.

I think the second thing that is really unique about Telix, and you're going to see it time and time again, we don't wed ourselves to a particular technology platform, right? We're targeting-agent agnostic, and we're isotope agnostic. We'll choose whatever we think is the right targeting agent that will give the best outcome to patients. We'll choose the isotope that we think will deliver the right radiobiology for the disease area that we're trying to influence. And I think that's the strength of the company. It means that radiobiology and just a broad understanding of regular chemistry is very fundamental to the DNA of the company.

In terms of our international growth. So this year is a pretty special year for the company. We have been, the last few years, essentially a single product, single territory company. We derive most of our revenue today from the U.S. U.S. market through Illuccix and now Gozellix sales, which actually formally launched today. We've been spending the last -- since we've got FDA approval a couple of months ago, we've been stocking pharmacies and getting everything organized for launch. That happens today. So coincidentally, by the way. We didn't -- it wasn't a crash timing exercise. It was coincidence.

But basically -- so we have that follow-on activity in the U.S. We've doubled down on product distribution capabilities through our recent acquisition of RLS. This is about building supportive pharmacy infrastructure for the long term, and I'll come back and talk about that a bit more in a second. But we've just recently received our GMP certification for our European manufacturing footprint. This is a massive capability that will enable us to service patients effectively in the European market.

We've also just recently taken over a partner site in Japan. So we now have cyclotron capability to service the Japanese market in the short and medium term. And then we've got a number of key strategic partnerships that are also -- we're heavily invested in, and we believe we'll be successful. We're running clinical trials in those countries to make sure that we have the data to get regulatory approval in some of those growth market opportunities.

So in short, again, one of our differentiations as a company is that we have the aspiration to deliver these products globally. We want to make a difference to patients everywhere that we can.

In terms of the U.S. market, which I know is a dominant interest in the room, we take a 2-track approach. We are heavily reliant on and will always be heavily reliant on quality distribution partners in the United States. It's a fundamental tenant of the nuclear medicine industry, bless you -- it's a fundamental tenant of the nuclear medicine industry. We're really fortunate to have outstanding partners that share the same patient-centric and quality values that we do. But similarly, as we think about particularly longer half-life products, and as we think about the transition to therapy, we believe that therapy -- large-scale nuclear medicine therapy will not be delivered without the use of practice of pharmacies.

We've got to combine traditional GMP manufacturing approaches with things that make it easy and accessible physicians to use our products. That means that you can't ship a vial to a customer, you have to -- you should be shipping a syringe. It should be ready to use. It should be dose calibrated.

And as Precision Medicine component of what we do evolves, it's going to be more and more important that, that package comes ready and calibrated and specialized to that particular patient's need. And so that's why we've made this investment. There's all kinds of good commercial reasons for doing it, but there's a long-term strategic viewpoint as well of what the RLS network delivers to us.

And then maybe just to sort of wrap it up a little bit in terms of how to understand the company, the first few years of our commercial trajectory was really about establishing all of the components of a commercial stage pharmaceutical company, which we've now done, I think, to demonstrable success.

We're now in the middle stage of the -- of our trajectory where we -- as we see it, we're diversifying our revenue streams. We're internationally expanding, which is also derisking the business because it's -- we end up with a multitude of revenue streams away from just the U.S. market. But the goal in this middle epoch of our growth trajectory is to be able to reinvest our earnings, everything that we've got back into that next inflection point, which is the therapy programs.

And I think you can see that in terms of our R&D mix, we've gone from predominantly preparing to launch commercial diagnostic products to now sort of 60-plus percent of our R&D investment back into the therapy programs. And so you're going to see as a consequence, and we've reorganized the business around these lines, as you can see from our org structure, to really double down and make sure that we're prioritizing the catalysts that come from that therapy pipeline development. And that's what's going to ultimately transition the company to the next stage of growth.

And so just to sort of give you a snapshot of that, how we see capital allocation and resource allocation inside the business is really this, what are the things that are enabling the business today to generate cash to be able to invest. Obviously, you're going to hear about growing our PSMA market, as Zircaix has a PDUFA goal date of August and that's going to be a very exciting follow-on product that's going to give depth. But then in terms of driving growth is really that, that therapeutic business, which we see as transformative for the future of the company.

Okay. So that's my opening comments. I'd now like to invite Paul to the stage. And I just want to say it's really a delight to have Paul here. I think what it does is it illustrates that when we acquire a business or we acquire a technology, we think very carefully about the people that come with that. And we make sure that we're not just integrating technology, but that we're really integrating the brain power that comes with it.

So Paul is a great asset, and you'll hear for yourself as he speaks.

Thank you for the kind introduction. My microphone is working just fine. Good. All right. Thank you. It's a pleasure to be in front of you all today.

And an important fact about myself before we get into the session and/or the question-and-answer period that's coming up, I just wanted to let you know that my hearing is not very good. So if you do have a question, please speak up because as my colleagues will attest, if I don't hear your question, I will very readily answer a different one. So it's an important fact.

So I'm going to be speaking to you about some of the trends we see coming down the road for radiopharma. And with my background, having in the last -- having just taken on the new role of CTO, spending the last 15 years leading the Life Sciences initiative at TRIUMF, Canada's national particle accelerator facility, along with the spin-off activity with ARTMS. With this bringing into the family of Telix represented an opportunity for me to focus on something exciting like what Telix is working on. And I hope to tell you a little bit about that today.

So my background is in chemistry, physics, a PhD in chemistry. And having led the initiatives that I have over the last little while, I feel I can bring into this company some expertise and depth on things like cyclotron accelerator targetry isotope production, radiochemistry and ways of attaching isotopes to biologics. But also to take physics and apply it ultimately to how we deposit energy into tissue. That's ultimately what we're doing.

We have tools and development, both in hardware and software, things that involve surgical devices or artificial intelligence that are coming down the pipe that will serve us well in this particular field. And I'm going to be working shoulder to shoulder with my esteemed colleague, Mike Wheatcroft, who is overseeing the biology biologic aspect, so tumor microenvironment, drug combinations and new biological target selection.

So this is a testament to the complexity of disciplines that are required for radiopharmaceutical development. It is atypical. And we have the depth of expertise, not only with Mike and myself, but others that are in the company, subject matter experts that I have the privilege of working with, that have an extreme depth to help guide the company through all of this.

And so the benefits of having these people onboard in-house is that they can help guide the company for the full preclinical to clinical translation aspect of what we do. The culture of just-in-time rapidly decaying drug product leads right into the research aspect of what we do, all the way through into patient delivery. And so if it's isotope production or drug delivery, we have experts in-house to help with that, but also the important things that generate intellectual property for protecting the company's ideas moving forward.

So one of the trends that I wanted to mention briefly was about isotope production. You've heard about the diagnostics aspect of what we started in, where we're moving toward in therapeutics. And when I wake up every morning, you might be surprised to hear that, I think of the world in different ways when it comes to radioactivity. So we have the diagnostic photon emitting isotopes. The world has long relied on things like Fluorine-18, highlighted in the left-hand column that was used for infra-imaging. But the company has significant plays, Illuccix and Gozellix with gallium-68 and Zircaix and zirconium-89. You're going to hear more about that with my colleagues coming up.

But in the therapeutic realm, there's a lot of work underway with lutetium. There's a product out today based on samarium. But as an example of looking down the road, there are isotopes like terbium-161. We want to make sure that if this isotope proved to be what it is that we're going to be ready to adopt it into the company's drug asset portfolio. That's because Telix wants to deliver the best isotope, coupled to the best drug for the best patient outcome. And that's really what we're after.

And if beta emitters don't cut it, then we're going to turn to alpha emitters. And so with actinium-225 and astatine-211, early -- closer to us on that horizon, there are other isotopes like lead-212 that we're looking at. And we have some really fascinating and amazing technology coming out. That is going to enable that isotope to be distributed and used more widely.

So ultimately, what it comes down to is we're producing and looking at isotope for their physicality and how they decay and what they're going to do to tissue and how we couple those to a biologic to deliver them. As the representative shows, you tether these things together molecularly and you want to deliver it to the target tissue and minimize off-target effects.

And I think touching again on that -- the importance of that culture of just-in-time and dealing with rapidly decaying pharmaceuticals, this is not a pharmaceutical play. This is a radiopharmaceutical company, and Telix has made some terrific investments to help that entire development pipeline, the manufacturing process, again, begins at the beginning.

And so with acquisitions like ARTMS and with ITG in Texas and Optimal in California and so on and so forth with the latest with the acquisition and onboarding of RLS, just shows the dedication that Telix has to starting early with isotope production, solving any problems, securing supply chain. Ensuring there's a robust reliable supply of those important isotopes, ensuring that the way we produce and manufacture formulate our drugs for delivery to the patient can be done reliably in a wide logistically capable net. So that's what RLS is. So again, the investments are a testament to what the company and this commitment is for delivering that reliable patient dose supply for years to come.

Now the portfolio currently is bookended by small molecule and antibody targeting agent. And it's important to know that in the research group, we're also looking further down the road as some intermediate platform represented on the graphic toward the right on this slide. And so with the acquisition of companies like ImaginAb, we bring in the capabilities of the Minibody, shown roughly in the center of the spectrum there.

And so with some validated targets there that may be important for us in the future in terms of other disease indications, we're also looking importantly at how these platforms can find a sweet spot when it comes to how they behave in the body, whether it's the fast and furious uptake of small molecules or the slow and precise uptake of antibodies. There could be a balance there that we could find with some of these other platforms, and that's what we're really pursuing there.

And so, yes, I think with the ability to also engineer those platforms to precisely take on the linkers and the chelators as well as the isotopes, we have the ability to potentially develop some very potent drugs. And so the R&D group is very keenly looking at this as well as other platforms through partnerships as it comes through the pipe.

And I just close out my discussion here with a fourth trend, and that's looking at dosimetry, and how it combines with emerging tools becoming available through our -- at our disposal. And really, what we're trying to do is, again, understand how the delivery of radiation to tissue represents the delivery of energy to the tissue. And so dosimetry is really the measurement of that, and we have people, subject matter experts on board that are looking at that closely. They are developing tools to basically take a diagnostic image, which is inherently quantifiable, I might add, and enable things like artificial intelligence and machine learning to take that quantifiable image and then apply it to how we dose and treat patients for specific conditions moving forward.

So really, the goal is to move from a situation today where we have image-guided dose imagery to really a computer-assisted dosimetry paradigm, where a computer is assisting a human clinician by taking arguably a larger than lifetime's worth of data and allowing a clinician to make extremely informed decisions about how to treat a particular and individual patient.

So this is really where we're pushing for a personalized medicine paradigm. And so this final slide just represents what I would envision happening in a future state where a patient comes in presenting with disease, there is an image that's acquired, that image is fed into an algorithm that is proprietary in nature. It is one that would help the clinician decide on which isotope and which radiopharmaceutical to apply based on the distribution pattern of the antigen you're targeting.

The patient would undergo his treatment journey. There would be a validation in mid-step about how things are going. And then the output would be brought into -- importantly into a data warehouse where there would be a learning opportunity. And there would also be ways to automate this process and to feed it back into the beginning of the process and to iterate this time and time again. So again, human clinicians, gaining the assistance of artificial intelligence and machine learning to make diagnostic decisions based on more data than what a single individual could encounter as an individual clinician on their own -- working on their own.

So in summary, I hope I've given you a little bit of a taste of what the R&D group is looking at. Importantly, it's to note that we are looking not only at the problems of today involving the short-term issues with the current asset pipeline, but also some product life cycle, but more importantly, looking down the road and strategically placing Telix as a leader in the field moving forward.

So with that, I'd like to turn it over to my esteem colleague, Kevin Richardson, to give us some more insights on Precision Medicine.

Thanks, everyone, and welcome. Let me just spend a few minutes I'll have with you on [Audio Gap] a couple of months of RLS and achieved 62% year-over-year growth, driven mainly by the 35% growth over prior here in the U.S., mainly driven by Illuccix cells on a quarter over prior year quarter growth. And then the sequential growth of about 9% quarter-over-quarter from Q4 2024 to Q1 2025. And that included about $33 million from RLS and as we closed that acquisition in January. So good momentum going into Q2.

So how do we get there? How do we do it? And really, how do we think about growing the Precision Medicine business? Well, it's really underpinned by the product offering itself. So establishing a foothold inside of the PSMA business with Illuccix. Chris just announced that Gozellix is initiating cells this month here at the end of June. And then really as we think about what that looks like with the rest of the portfolio that will go in a little deeper, we really think through the life cycle management of really just -- not just PSMA, which we have some really exciting things to talk about today, but as well as our other product lines, too, in that product. So the growth strategies depend on the product.

And then we really think about then what do we do with that product. Well, we take it to other geographies. So we continue to -- and you've seen some of these disclosures, we continue to do the global rollout of Illuccix. If you're not flag chart savvy, we'll have the names here in a little bit. But we plan to continue to roll that out through my counterpart, Raphaël Ortiz internationally.

And then finally, we will continue to file on the other products that we're bringing to market initially here in the U.S. first. And then we take that bundle of products, and then, we expand the use of that through indication expansion. So we'll talk a lot more about that on the PSMA side with some exciting news, but we have those plans across all of our product franchises.

So if you think about just those 3 things, expand, expand, expand, what that really does is it shows the perfect marriage between our Precision Medicine business and our Therapy business because in each of those markets, we're building key relationships with regulators, with payers and customers. And we're preparing and building that road, if you will, into those markets as Richard talks about in a minute how we're going to bring those into each of those markets.

So we're -- we have great relationships built, great respect for each other in the relationships that we're building with the regulators and preparing the way for them. So then the question is then how do we deliver those products, that indication expansion in those new geographies? How do we deliver that to the market and achieve sales performance or success? And a lot of that is about building these commercial customer-facing teams that are true specialists.

We take a modular approach to that, where we have market access, people to help with reimbursement. We have clinical people to help with the clinical science. We have the sales and marketing people really to understand the value proposition and our message. And ultimately, we bring that to bear in each of the markets that we play. So we have a tailored commercial playbook in each market, not only internationally, but even here in the U.S. because there's many different segments of the market that we have to think through, and then, we have to deliver that value proposition in a timely and frequent basis.

And what's happened over the last 3 years is that we've really developed a reputation in the marketplace for an innovator. And so when you really talk to customers about what Telix is and what they represent, it's about innovation, it's about service and about reliability. And so we've really built this Telix brand as we prepare the market. We built it on Illuccix, and it's prepared now for our follow-on products that we're talking about.

So to go a little deeper on the products, on the growth strategy, you've seen the slide before. We have successfully launched our second PSMA product and -- in the prostate market. We'll go deeper on that. We have a PDUFA date in August for our kidney product or our CA9 target. The brain product or our Pixclara product, as you know, we made an announcement on a CRL for that, and we plan to keep progressing that forward and submit sometime in 2025.

So a little bit deeper on the expansion or growth strategy on the global rollout, you can see from the map on the left that we definitely have underpinned it here in the U.S. We have plans across Europe, more really focused on some of the key markets like France and Germany and the U.K. But of course, there's 10 additional European member states that have got approval, too. And if your eyes are good, you can read them at the bottom and that will explain the flag chart from before.

As you move over further east, we're really focused on China and Japan, where in China, we have completed our registration study, and we're preparing an NDA there. Our Phase III study for Japan is just initiating. And then finally, to kind of round out the Americas, we have the first approved product for PSMA PET in Latin America, and we've commenced commercial operations there with our partner.

So then we go to that third leg of the growth strategy. We take our products, we take our geographies, and then, we add new label expansions. I'm going to go a lot deeper on PSMA PET. We've got some exciting news there. But when we -- once we achieve approval for our Zircaix product, we'll initiate the Zirmet study, and that is to take it from a diagnostic perspective into a metastatic perspective as well for reoccurrence in clear cell renal cell carcinoma.

And finally, when we -- after we submit and achieve approval for our brain product, we will continue that label expansion as well, not only into diagnosis of brain mets, but we're also looking beyond glioma itself. So what does that really look like as you kind of wrap this strategy together? So it was to really establish ourselves by launching Illuccix, and then, launch Gozellix. If you've had a time to kind of chat with us a bit, we say that hope is not a strategy. We plan very specifically for our second launch to achieve concurrently with June. And then as we start thinking about what PSMA looks like, then we start thinking about the other opportunities inside label expansion through KOL engagement and really through guideline expansion.

And no, you're not reading a typo on what we think the TAM can be. We think it can go up to over $6 billion. And if we've had a quick conversation, many people have asked me about what do I see the PSMA market doing. I said it's large and getting larger. And some of that is through what I call PSMA confidence, where physicians are just using it earlier and more often, but we also have some exciting programs on label expansion that we think will drive us to that $6 billion-plus market.

So before I go into that, I'd just touch really quickly on Gozellix. We are the first company to really have 2 products out there, and we really feel as though the 2-product strategy is important in this time. We have what we've given the customers' choice in terms of economics or they can choose flexibility of scheduling. It's got a higher activity that we're able to put in. So it gives it more -- and we have more stability so we can take it further.

So the reality, Gozellix fits into 2 markets. It fits into the urban market, where you can have timing and flexibility with the patient scheduling. It fits into the more rural areas, where we have what we would say is a distant PET strategy. There's approximately 3,000 PET scanners in the U.S., not all of them are utilized for PSMA because you just can't get the dose there because it's just too far away from the manufacturer point.

One of the benefits of our reliability and availability is that we have 266 points of manufacturer dispensing and distribution. Chris showed you the map a little earlier. That puts us right next to our customer base and so that gives us that high level of reliability. But there are some scanners that are even beyond that point that now with Gozellix we can reach. We believe that represents about 10% of the market and -- 10% to 20%. And typically, it's an underserved population that just typically doesn't want to make that drive into where the PET scanners are. So we believe it really enhances reach and customer service, both in urban and rural areas.

So now just a few minutes diving into the patient journey, if you will. So our TAM that exists today is about $2.5 billion to $3.5 billion, and that's driven by the current label. So our current label is initial staging prior to definitive therapy and suspected reoccurrence and then patient selection for radioligand therapy. The additional indications that we think will expand through confidence, AUA guidelines, SNMMI guideline expansion and ultimately NCCN guidelines, we think can add to that as well in both managing and monitoring response to therapy as well as managing progression to therapy.

But what does that look like? So where does that TAM kind of build in? So I'll show you the TAM that we typically show, but I wanted to kind of show you the patient journey, so you kind of understand where we see the TAM going. Most of the TAM is in reoccurrence. So if you look at indication #2, that's the biggest bulk of patients that we have out there that were -- that physicians are referring for and that we're scanning for.

But I think what we really want to talk about today is how do we get at the front of that. And through what we think is going to be a well-designed study and well-executed study, we'll be able to achieve a diagnosis indication that talks about diagnosis for prostate cancer through PET imaging.

Now if we can put ourselves at the front of that scan, that's also a great value proposition because we believe from a marketing perspective, that's a -- we would call it a sticky position to be in. Most physicians are going to want to use the same scan throughout the patient journey. And so the existing TAM is still there, and we will be able to take that patient from diagnosis all the way to monitoring to progression, as they go through that time.

So when you put that in the way we typically show the TAM. You can see that it basically doubles the TAM and puts us right at about $6.7 billion of available opportunity out there. And then the indications in pink are the 250,000 scans are really the AUA guidelines, the SNMMI guidelines and really the expansion inside of what we're doing today.

So before I turn it over to Dr. Liu to go in a little bit deeper on the study, we think that there's -- we know there's over 1 million men that get a biopsy every year. And really, when you think about what it takes to be disruptive in this space and innovative, which we think is part of that Telix brand that you have to minimize patient trauma, we think you'll see that; reduced recovery time, we think you'll see that; and we think it will lower cost while improving outcomes. And that's a really important thing to really change and be disruptive in this marketplace.

And so I think what many of us will see today is that we're going to have a choice in the future. If you're a man, and at some point, you may have a high PSA and need a biopsy, you would either have to decide whether you want this, and David will explain, or you get an IV, your choice.

But thank you for your time. I'm going to turn it over to Dr. David Liu, our Chief Medical Officer, for Precision Medicine.

Thank you, Kevin, for the introduction. And I really appreciate you being a participant and volunteer for our audience participation portion of prostate biopsy, although you sat down. So I guess we'll have to wait until next time.

So good morning, everybody. My name is Dr. David Liu. I'm the Chief Medical Officer for Precision Medicine. I'd like to take you on a little bit of a journey and just to give you context and color as to how we got here. So when I started my medical career 25 years ago, the diagnosis of prostate cancer consisted of a digital rectal examination and a needle mounted on your finger. When around '86, '87, ultrasound-guided biopsy was introduced. Around 1994 [Technical Difficulty]. In 2011, MRI then became kind of the complementary standard.

So as you can see, we've gone through various epochs of [Technical Difficulty] denominator. And that's this. Now I can see about [Technical Difficulty] in the room just jump right there. This is a biopsy gun. So what we do nowadays is when we have suspicion of prostate cancer, we either see a lesion, and we target that lesion, or in the vast majority of men, we actually perform -- we perform what are called systematic biopsies.

And what systematic biopsies are [Technical Difficulty] these as an example, 1 millimeter in diameter, 20 millimeters in length, and we do that 12 [indiscernible] in your prostate. How do we do that? Either by placing the needle through your rectum transrectal biopsy, through your perineum, which has other terms, but it's basically the space in between your penis and your anus.

So you can see that our evolution really has been the final destination being a prostate biopsy. And the reason for that is because we are [Technical Difficulty] the gap and the deficiencies that we have in conventional diagnostic imaging.

What issues do we have with prostate biopsies? We have 1 million men going through this with anywhere from 12 to 14 to 40 biopsies in a single setting and potentially you rinse and repeat that every year. So the first issue is compliance. Up to -- of these 1 million biopsies, up to 25% of individuals actually decline the biopsy for the various reasons of why you jumped when you heard that biopsy gun because this is not a low-risk procedure. It is very [Technical Difficulty]. You can demonstrate it in the room. It's very anxiety provoking.

So compliance is kind of is a good portion of that. And we can actually address the anxiety, the stress and the diagnosis that would, otherwise, not have received adequate early diagnosis and adequate treatment. So of the 1 million biopsies that are performed, 75% of them are duds. 75% of the [Technical Difficulty] of prostate cancer. When we have these recommendations, they're oftentimes based on the imaging alone, and we actually have no molecular profile.

So as I mentioned before, the stage of disease is based on different factors. One factor is where is the disease gone, is it within the prostate or spread out. And also the molecular footprint or characteristics of which we use, which differentiate between clinically significant and insignificant cancer. We use a score called the Gleason score, which is essentially looking at mitotic rates within the prostrate itself. We don't have that information.

So in the net-net of it, we have too many men receiving too many prostate [Technical Difficulty], too much tissue, and we aim to change that. We have the goal and ambition of transforming the way that prostate [Technical Difficulty] and thus introducing the fourth epoch of prostate cancer screening and diagnosis.

So this is what the [Technical Difficulty] individual men are referred for biopsy and/or referred for MRI based on symptoms or elevated PSA or strong family history, basically predisposed risk factors. They'll receive an MRI, which will then stratify them into a PI-RADS score. A PI-RADS 5 is basically a diagnosis of prostate cancer, high suspicion. PI-RADS 3 to 4 is this intermediate to high-risk category where you see something on the MRI, it kind of looks like cancer, but we're not quite sure [Technical Difficulty] pretty sure. And then the PI-RADS 1, 2 category is either [Technical Difficulty] absolutely normal prostate. A PI-RADS 2, demonstrating findings within the prostate, which are actually of low risk for cancer.

And each of these 3 categories is addressed in a slightly different way. For the PI-RADS 1, 2 patients who already have risk factors for prostate cancer, they will likely not undergo biopsy, but they will actually have continued surveillance. And this introduces a degree of stress and anxiety and really the risk of undetected prostate cancer. We know that these people are at risk. We know that there's a good chance that they have a prostate cancer. And all we're doing is we're just watching through our imaging modalities until we see it.

In the PI-RADS 3 and 4, generally speaking, depending on the level of confidence that we have, we may potentially target a specific area within the prostate or we may perform these systematic or saturation or template biopsies, which are these multiple random passes -- or not really random, they're anatomically passed through the prostate. And we basically are just trying to sample and see if we win the lottery to find the incidental prostate cancer that we can't see.

And then, of course, with PI-RADS 5 with a high confidence of there being cancer, we need that tissue diagnosis to be able to differentiate, but we also need a PSMA scan in order to stage as well. So different journeys for all these individuals, but you can see the common denominators that [indiscernible] of anxiety and really the biopsy is being driven by the fact that our imaging modalities are inadequate.

We intend to change that with a new study, a clinical protocol that we've submitted. The IND has been submitted. It's going through ethics review, and we certainly look forward to the announcements of our first patients being enrolled.

What we've really done is we've really tried to rethink and reinvent the way that prostate cancer is diagnosed. [Audio Gap] the molecular probes that we have using PSMA 11. And with this, we can then stratify these into 3 slightly different categories. Those that have potentially high risk in the PI-RADS 5 category, we would perform an image-guided biopsy, but a very, very precise one and simultaneously be able to look at staging and surgical planning. So in other words, rather than getting a biopsy, diagnose and then a PSMA scan to stage, we can do it all in one fell swoop.

In those individuals with PI-RADS 1 to 4, now we're aggregating basically anybody that gets an MRI that has a positive lesion, we can actually perform a precision biopsy. Because we know that PSMA is much more sensitive in the detection of prostate cancer, we can then perform a one and done. In other words, rather than the 12 to 40 biopsies, we can do 1, have the histopathology, stage simultaneously and move on to the next step.

And most importantly, for those individuals with PI-RADS 1, 2, in other words, a normal prostate with risk factors, if they demonstrate a negative result, in other words, no uptake of PSMA, we can now go from having to do these template biopsies or giving them the anxiety to wait until the next year's cycle to no biopsy at all and perform a none and done.

So we've really been able to transform and reinvent the process in which prostate cancer is diagnosed. And this really means that we -- that with this study, we will improve predictive accuracy, we will reduce the number of biopsies from up to 40 down to 1 to 2. And we -- and for some people, for some men, we may actually eliminate the need for a biopsy altogether.

And as a result of this, we decrease the risk and anxiety and stress involved in an ambiguous diagnosis based on inadequate imaging modalities. And this really enables clear treatment stratification. It enables a personalized diagnostic journey and really an expedited process from diagnosis to staging to treatment. So no longer is it going to be a turn style of coming back to the hospital over and over again to be able to get the next stage of test and the next stage of test. We're really doing it and addressing all these issues in one setting.

So the study that we are actually implementing really is going to address these PI-RADS 1 to 4, which is basically the majority of people. And then looking at stratification, the positivity of the PSMA scan to determine whether it's going to be a one and done or a none and done scenario.

So when I look at the patient's journey and the accumulation of my 25-year medical career, what I realized was that what we've actually been doing is we've been repeating. As I alluded to before, addressing the inadequacies of conventional imaging as a result by performing these biopsies. And in this cycle, in this turn style, in this rinse and repeat cycle, for those individuals that have biopsies that don't demonstrate a prostate cancer, they undergo the same thing the next year. They get another PSA, they get another MRI and they get another series of biopsies.

So not only is this cumulative with respect to the initial diagnosis, but as Kevin had mentioned, there's also the stickiness factor, where with this single diagnosis and staging modality, we've now not only decreased the requirement for repeat biopsies, but we can now stage, monitor and potentially treat with our therapeutic pipeline.

So we've gone from a finger to various imaging modalities, above you can see what the ultrasound looks like with Doppler applied, and I would challenge many of you who are in the nonmedical in nature to identify where the prostate is on that image. And in fact, to make it even more difficult, here's the MRI below, which is actually a little bit of a molecular probe looking at protons and proton density and behavior, find the prostate. A little bit harder to see.

In the bottom, which is where we are now with PSM imaging, not only can we find the prostate, but I think it's pretty obvious where the cancer is. And that's the type of fidelity that we have and the confidence that we have in diagnosis based on implementing these types of molecular probes to really, really look into the biology and behavior of disease.

And simultaneously, as I mentioned, with the PSMA scan, we can also look at the whole body to look at immediate staging. So, therefore, there's no ambiguity with respect to the presence or absence of more advanced disease, the determination of whether local curative intent or potential systemic therapies, such as in our alpha and therapeutic programs may be most appropriate.

So 2026 and beyond with the successful implementation, execution and readout of our clinical study will really change the paradigm of how prostate cancer is diagnosed. For those that are at risk, either due to elevated PSA, clinical risk factors or clinical examination that's suspicious for prostate cancer, the combination of an MRI plus a PSMA would really eliminate the need for biopsy in approximately 40% of those individuals. Also instilling confidence in those individuals that they're not in this stressful purgatory of whether they have cancer or not.

And for the 60% of individuals of men that do require a biopsy, no longer do we need to do the saturation, systematic or template biopsies, where multiple biopsies are performed, but we can be very precise, and we can really with -- no pun intended, but with surgical precision be able to localize, diagnose and prognosticate for these individuals.

So I think -- I hope that in these last few minutes, I've been able to present to you kind of the narrative with respect to how this complicated topic of trying to compensate for inadequacies of imaging is really solved through the introduction of this PSMA protocol and study.

Now furthering our relationship with the urologic and uro-oncologic community is critical. And I think it's a perfect segue to introduce our CA9 or carbonic anhydrase 9 asset, otherwise known as Zircaix. And what this is -- as many of you know, is zirconium 89, which is the isotope attached or linked to girentuximab, which is an antibody that targets carbonic anhydrase 9, which is associated with upregulation of angiogenesis, which is part of a cycle of cancer. And it's present in 95% of clear cell renal cell carcinomas.

You're aware of the ZIRCON study, our Phase III clinical trial that reported out sensitivity and specificities of 86% and 87%, really a blockbuster diagnostic tool. And what this really does is it mitigates the risk of biopsy in the kidney. The kidney is a highly vascular structure. 10% to 15% of these lesions are very, very difficult to biopsy and about 5% of them bleed to the point where an intervention is required. The bleeding itself is not only a factor with respect to immediate management, but also tumor seeding.

So you can see as an interventional radiologist, as somebody who has had the lived experience of dealing with these complications in the patients that I'm trying to help, it's not a good feeling, and it's not necessarily an exciting part of my practice before renal biopsies. It's with a lot of hesitancy. So really, the ZIRCON trial, the Phase III clinical trial is truly practice-changing.

So in the setting of clear cell renal cell carcinoma, we really do have that unmet need. Once again, the narrative of this is that the biopsy compensates for our inadequacy of imaging. And with these types of targets, whether we're talking PSMA or CA9, we're really actually doing these molecular probes to be able to perform almost a virtual biopsy. We can get the diagnosis without doing the intervention. So this decreases the unnecessary surgeries, decreases the potential complications of bleeding, as well as tumor seeding. So really changes the way that we look at the diagnosis of renal cell carcinoma.

In those individuals with Zircaix PET positive lesions, we reduced the time to diagnosis. We don't actually cause an intervention that could cause further consequences and complications. And in those individuals with Zircaix PET negative scans, we've now changed those individuals' status from ambiguous, not sure, to a lower probability of aggressive disease. And as a result of that, really putting this front and center in terms of the assessment of renal masses is going to become -- I'm very confident saying, is going to become, and should become, the standard of care before biopsy.

And I think with that background, because I know we have a very learning audience with respect to Zircaix, I'd like to hand the mic back to Kevin to address some of the opportunities that we have with this asset.

Thanks, everyone, and thanks, Dave. Just to finish out the Precision Medicine piece, kind of back on the commercial piece and what we're really trying to do with the patient population. And we're really committed, as you can see, to the renal cell carcinoma patient. And -- but it really aligns with the way that we treat all of our patients and it aligns with our commercial strategy. And because of what Dave just went through, we believe it does enable first. So we're going to enable this biopsy replacement even inside the kidney, with an indication of really diagnosis and characterization.

And then like I had mentioned before in the growth strategy, then we want to grow that, both through just increased market adoption, we showed you the TAM for that a little bit earlier, and through guideline inclusion. Really, we've got a lot of work that we've done there and then label expansion studies through Zirmet.

But then we believe this is a transformative target. So we believe that the CA9 target expresses in cancer across, and we think that we've got really good data that we're generating concurrently through some ongoing studies that we have right now. So we believe that in the CA9 program that we will enable it, we'll grow it, and then, we will transform it.

So that's the way we see the TAM, as we think through just the diagnosis and characterization of clear cell renal cell carcinoma. And then we believe that there's the potential new indications of metastatic disease that we talked about with Zirmet, and we believe that, that TAM is $750 million plus that we have the opportunity now. Again, one of the exciting things commercially is we're the first one to market with this. It is practice-changing, we believe, through David's comment, and we're excited to get this to market.

So how does that really kind of work inside of what we would call the Telix portfolio, or the Telix bag, is that many of these patients start in your PCP. After some sort of test or screening, they move over into an imaging, either through urology or a radiologist with the nuclear medicine. And then when they continue down that pathway, they get into treatment or management through a urologist, a MedOnc or RadOnc or an interventional radiologist is involved in that as well.

So what's nice to see is that lines up perfectly with what we're doing inside the prostate business and that we've already been building relationships and building confidence and building that critical mass inside of that urological call point. Across all of those diseases, both those diseases and the specialty of really urology is kind of the main point in there that is referring those patients.

So with that, I'd really like to dive now a little bit deeper. We had a big deep dive into prostate and into our biopsy program. I'd like to turn it over to Dr. Joe Osborne, who is the Chief of Molecular Imaging and Therapeutics, and he is a Professor of Radiology at Wild Cornell Medicine. So thank you, Dr. Osborne.

So today, I'm going to talk about Zircaix. But before I start, I want to thank Telix leadership and also give a bit of a personal perspective of PSMA because that is really what has happened across my career.

When I started in 2008 as a molecular imager, before I was chief, I was just a junior attending. When we came to the GU management team group, we were basically the ones who were supposed to bring the snacks and look at some of the images that no one could interpret like the ultrasound. And so they kind of had us there, but we were -- we didn't really have a role.

At this point, very recently with PSMA, our urologists and medical oncologists and maybe we can have -- can we have like a specific hour like an additional meeting so we could go through all the PSMA scans because an hour is not enough. And maybe then we could also talk about some new trials and some things with the Zircaix on another meeting. I'm like no, like 3 hours, we can't do it. It's like too much. But I know with everything with my chairman, no is not the right answer because we just are going to need a bigger boat.

And everything that's been described is the expansion of the really exciting things that have happened in my career that included PSMA. But also, what I'm going to talk about today, which is Zircaix, which is the future, which hopefully -- and certainly, the other people of the GU management team group hopes will expand as quickly as PSMA has really changed our practice. We do things completely differently from the way that we did 10 years ago. So for Zircaix, that is also important, not just for my career as a clinician, but I'm a clinician scientist.

So these are things that we were talking about for years. We're talking about antibodies and their specificity. We're talking about zirconium-89 and the ability to label these antibodies so we would get not just the specificity, but also we would be able to look at the finding specifically.

And we were talking about it for years, but we didn't know whether there was going to be a group that had the flexibility and really, the growth that Telix has had to really take this product, take it, have the big trials and actually find that it was useful and have the flexibility to change, right, because we knew there were many different ways this could go. We didn't know what it was going to be, but we knew something had to change.

And the reason we knew things had to change, this is also part of my training, during the time, and this was in the early 2000s when I was a radiology resident, we were getting better and better at CTs and MRIs. So back in the '70s, there really weren't many renal cells being diagnosed because we just didn't have the machines.

When I was training the machines, [ forced ] ICT, 16, 64. And then by the end of my residency, we're like, "Okay, we're seeing all these renal masses. But what are they, right?"

And really, that's a conversation that we have to have with patients. They don't want to hear necessarily about the sensitivity and the specificity. They want to know once something is identified, what is it? "You've told me I have something, what is it going to be?" And that's where we came in as molecular imagers.

So they first asked us, well, what can we do about it? Can we use the regular FDG PET. It turns out that's not good at all. And we had to say at the time that well, there's really exciting stuff on the horizon. It's going to happen. It's really going to happen where we're going to be able to have that kind of specificity that's going to change these conversations with these patients where you could say, "Okay, this is -- we've seen it, and this is what we're going to do."

So the unmet need for the diagnosis is about these conversations. It's about the conversation of finding these small renal masses and saying, okay, well, before things progress, we want to deal with this definitively. We want to deal with it. Do we have to biopsy it? Do we have to do something specific or even worse, the number that's on the bottom of this slide?

If you if you have 30% of nephrectomies come out with benign lesions, is this a conversation that you want to have? We did a nephrectomy, all these things happened. And by the way, it turned out, yes, it was benign, it was actually fine. We didn't have to do all these things.

What they want -- what people want to know, and this is what has happened through the trial and the specificity of the numbers, and decreasing these non-diagnostic biopsies, decreasing the need for the nephrectomies. You're able to get to the point where you can see that image, you could see that hotspot and have a very good sense with specificities that really start in '86 and '87.

But when you look at this, even smaller renal masses even higher and being able to tell people, "Okay, this is what we see," and this is in the '90s, which is really as good as we get in terms of sensitivity in medicine. It's the kind of number where you could have a conversation and say, "Well, anything is possible." Yes, it could be something that's within the 2%.

But that's not what medicine is. Medicine is getting you to the above 90% confidence number, where you could say, "This is what we think non-invasively, so we don't have to proceed further with the next step," which could be a biopsy or a nephrectomy.

And this is just going into the numbers with the renal masses because this is something also in my training, which was unclear. You find something really small. Is it small, at benign? Well, we used to give a differential. So there were things that we knew what they were. Okay? This is in AML. This is a small cyst. Okay, then there's this like 80% that could be all these different things. It could be like an oncocytoma, you don't have to do anything.

But actually, it could be a clear cell renal carcinoma that you might want to actually jump on right away, but we weren't really sure at the time. So we were just giving them impressions that you never want to give as a radiologist, which is, number one, no [ apeticize ]. Renal lesion of uncertain significance and behavior follow-up in a year, and you would get a call and they were like, "Really? What does that mean?" It means I'm not really sure.

And so that's where the molecular imagers came in because we had to give a little bit more certainty. But of course, where does that come from? It comes actually from Telix and actually running the trial because you have to know if you're getting to those numbers and getting to that level of certainty.

That is a very hard trial to run, right, because getting to that level of sensitivity and specificity and making decisions based on it is -- means you need to have the just right antibody, or just right vector. You need to have the just right nuclide. So with zirconium, which has a [indiscernible] 3.3 days, that's going to be around the time of the circulation of antibody.

Perfect. Antibody very specific and you're looking for a surface molecule that is going to be a differentiator, something that is on a cancer cell but not on benign. And that's the body. The body does that. You just like hope to find something that's a surface molecule that's going to do that.

And that is actually what was the driver here in getting to these numbers, where you have an under 4 centimeter lesion with the sensitivity of 85%, specificity of 90% and less than 2 centimeter at 97%. And so with that, you could say with these uncertain renal lesions, you could get to the level where my GU oncology group is happy, right?

So when they ask us what we see and then we see what is in this case, which is something we see all of the time, where they say, "Okay, so smart guy, like we done the PSMA scan, that's really helpful. But you know what, a lot of these gentlemen who are in their 70s. Now they have a second cancer. So is that a second cancer? Or is that cyst? What's going on there?" Because you don't want to solve one problem, and then have another one just faster and then the person actually has a consequence of the second cancer.

And so in this particular case, when PSMA could not provide the answer, the girentuximab did, right? So you could say, okay, it's a small renal lesion. So we could deal with both the prostate cancer, and we can deal with the renal cell and then put the patient back into the area of some certainty, where you can do follow-up without doing something more invasive.

And then there are these lesions. And these particular lesions and these images right here have the -- our colleagues, the interventional radiologists, they were all just like, "We could read this. Like do we really need you? I mean we could find something like this across the room, especially when it's like an anatomic shaded surface display."

They're like, "We're actually better with the anatomy because we actually cut people open, we do people biopsies." So then we'd be saying zirconium-89 and they're like, what's that? Kind of like job security. But you definitely want to have this kind of image to convince.

And patients actually love this, right? When you can bring them into your office and say, we did a scan and we saw this. They love it when there's something more definitive than a scan that even like the ultrasound that even the imagers didn't want to look at. This even the patients will love.

And then I'll leave you on this because this is also equally important. If you see something on a scan and it's a size of a baseball, when you're having a conversation with a patient and you're like, "Yes, there's this baseball size thing on your kidney," it doesn't go well if you can't say is it good or is it bad. I mean baseball always feels like bad, right?

But if you can then do the scan and show that it's this lucid lesion without uptake with a specificity in the '90s, you're like, "Okay, well, I'm not 100% sure what it is. But what I can tell you is this not going to be a clear cell renal carcinoma that at the end going to metastasize and then you're going to have 5 months of chemo and suffering and everything else, and we can do a number of different things," so the conversation completely changes.

And I think this is one of the things that people actually like the most, like knowing that there may be something, but it's not something that has to be dealt with aggressively. Thank you.

And have -- then have a presentation on 591 and then we will take a break for coffee and morning tea, so for those who need some caffeine. But I'd just like to call up to the seat Dr. [ Joseph Osborne ], thank you so much. David, Kevin and Chris.

We've got a couple of microphones. If you have a question, please raise your hand, and we'll get a microphone to you to ask those questions.

Brandon Carney of B. Riley Securities. Just on the biopsy use case here. Just wondering, how useful MRI has been in guiding those biopsies? And if that itself has been able to reduce the number of sample sites?

And then also what the potential for PSMA negative disease is? And how that plays into the potential of those scans in the early cases?

Sure. [indiscernible] So with MRI, we are able to -- it's more of an anatomical probe. So although ultimately, there are some aspects to cellular density that we can examine, the PI-RADS stratification is really just a risk stratification scoring system.

So for those individuals that have PI-RADS 1, 2, which are the ones that have -- which -- with risk factors, they generally have somewhere between 20% to 30% of [ adult ] disease. In other words, they have prostate cancer somewhere we just don't know where, we can't see it.

So the overall diagnostic performance of MRI, if we go across the board for those individuals that are at risk, is about an accuracy of around 65% to 70%. So we miss about 35% of cancers.

Now as far as the targetability, if you do have an individual that demonstrates these PI-RADS 3, 4 and 5 categories, which really give you an atomical target to biopsy, they do actually -- it may potentially decrease the need for the saturation or template biopsies depending on the PI-RADS score. So PI-RADS 5, for instance, has a very high probability, 80-plus percent of it being prostate cancer on the MRI. And therefore, you may be able to just do a single biopsy in that setting.

However, and this is kind of a further discussion that we're having in regards to the life cycle management of PSMA, sometimes biopsies are performed in order to provide information on the neurovascular bundles and proximity of cancer to the neurovascular bundles.

So this is what it's referred to as nerve-sparing surgery. And what nerve-sparing surgery does is it preserves a man's ability to achieve and sustain erection. So it has major implications to the health and welfare of men in the future.

As far as the implementation of PSMA, time and time again, it's been demonstrated that PSMA across the board has much greater sensitivity in the detection of prostate cancer.

There is a defined population in the single digits, about 5% that are PSMA negative in terms of their expression. And that's one of the reasons why we're looking at this at as a strategy as an adjunct to MRI. In other words, we're not seeing that PSMA is better than MRI, this is like peas and carrots. They're better together than they are individually.

Not sure if Dr. Osborne, if you might have some comments?

Yes. I think that there was a time when people -- the MR community, the molecular imaging PET community would believe that their modality was going to solve everything. And I would -- I think the -- it doesn't, right? There -- as you said, there's better together.

There are ways and there are aspects of the diagnosis, where you're -- at any -- then, you're really trying to get to clinically significant disease. Like what is this going to do? And there's aspects of anatomy that gets you to that because there are -- especially with surgery and with procedures, there are adverse events that you want to avoid.

There's also the likelihood of it being aggressive, which you might see with PSMA and some other modalities. When you put them together, especially if it's something that's noninvasive in its diagnostic phase, is incredibly helpful. So these days, the MR community and the PET community are kind of getting along a little bit better because I think there's no way to have one without the other.

Even integrated machines.

And with integrated machines. So we have 3 [indiscernible], which we bought at Cornell in anticipation of this. Although an interesting aspect of it is sometimes even though they're better together, sometimes as a single machine, not quite as good. Although I don't -- my Chairman bought that. So I hope this like video goes nowhere. But yes, it has actually driven device development because it's believed that that's going to be the way forward.

Okay. Great. So yes, Dave [indiscernible] from UBS. Just a couple of questions on the commercial aspect of Illuccix and Gozellix.

So we know that Illuccix will -- there [ hasn't ] been pass-through, will expire end of June. So how should we think about potential impact on the top line for Illuccix?

And then for Gozellix's commercial strategy, any kind of thoughts around cannibalization of the existing Illuccix market?

Maybe I'll open it up and then hand it over to Kevin.

I mean our guidance for the year is based in how we feel we will transition through that pass-through period. We have the benefit of being in the mid budgets, in the mid-commercial cycle for a year. So we've been able to manage that process proactively with our customers. We're going to know in a couple of weeks' time where we stand on pass-through. So that helps with respect to things like temporary coding in the interim.

But also, it's a really dynamic environment right now. And so we feel that we've got a lot of momentum going into the Gozellix launch. Our customers understand not just the [ advantage of ] Illuccix but also the real benefits that Gozellix brings as a follow-on product.

I don't know if you want to chime in.

Yes. I say many times that this wasn't a surprise, like it seemed to have been. We've been planning for this for 3 years and have worked Gozellix to the point where it's launching basically this month. So to Chris' point, we planned for this proactively through the next 3 months, and we've got the teams out executing that playbook in those particular accounts.

Just as a reminder, not every patient is a CMS patient. And not every patient of that age is under normal or regular we call traditional Medicare, they might be under Medicare Advantage. So we are managing that on a hospital-by-hospital basis or IDN-by-IDN basis in our contractual language. So again, not a surprise. We're planning for it. The guidance is based on that. So we feel comfortable with that.

Rich Newitter from Truist Securities, and thank you for hosting this day. I have two, just maybe on the piggybacking off that commercial question on Gozellix and Illuccix.

You made a use case for -- Gozellix is going to allow you to extend your reach to harder-to-get-to areas, a huge underpenetrated market, I understand that. But just from a pricing standpoint and institutions, not the ones that are hard to reach, where it sounds like Gozellix is the solution, but where you actually have customers that might be thinking about using one or the other in different portions of their patient population, Medicare versus not; how does price differentiation work there, if at all? Can you just talk about what's involved in terms of getting both products on formulary and to make sure that it's a smooth process? And I have a follow-up.

Yes. I mean it's [Technical Difficulty] products -- sorry about all the audio problems we're having today.

It's erroneous to think about the two products as equal. They're not. They have really different characteristics. They allow very different scheduling flexibility, the way in which we deliver product to the site in terms of the dose volume that's available at a particular point of time is completely different. And so we think it's fair to garner value for that.

So it's really a good way of -- if there's a concern about what's the basis for pricing differential, it's really about pricing service, and it's manifest in the product itself. And they'll exist side by side, just as PSMA agents exist side-by-side today from a billing and an ordering perspective, there isn't a lot of magic to it.

And it will just come down to preference based on the patient category and probably above all else, preference around scheduling and patient management. I don't know if you want to add anything or?

The only thing to add is that these are most often urban centers, they're sophisticated ordering and delivery systems and well set up to be able to manage two products that are that are for a similar patient but definitely for a different reason based on the hospital and what they require.

Anthony Petrone from Mizhuo. Thanks for hosting us and appreciate all of the detail on the pipeline and the existing product portfolio. Maybe just a quick one on Gozellix, just the update on the transition pass-through status, code timing. So that will be one.

And then going to biopsies. When you think about NCCN Guidelines, I mean, what type of clinical program is going to be needed to sort of secure guidelines to maybe have PSMA PET replace some level of biopsies?

And you also mentioned this 3,000 PET scanners in the United States. Just wondering, what do you think the PET scan capital capacity is going to be needed over the next few years when you think about expanding not only the oncology side of the equation, but we're seeing cardiology in other areas?

Yes, there's a bit to unpack there. Maybe I'll start and if you want to handle the timing on the reimbursement.

No, I just think that -- so this is -- the biopsy study that we're talking about is a Phase III trial. It will be an extensive protocol. We'll obviously be socializing the details of that as the IND gets approved. We have had -- it was a heavily consulted protocol from a regulator engagement perspective. So we're filing the IND with confidence that it's a protocol that will be accepted.

I think everybody in the room understands that biopsy is a challenging topic, right? So moving up into that frontline of use of imaging is clinically contentious. And so we've got to make sure that the protocol is well thought out, and I'm convinced -- you've seen the chubby brain in the room. I'm convinced we've got the right people that are in behind that. So that's, I think, the answer to that question.

And then from a machine capacity perspective, there's a huge amount of pressure to expand the service provision of PET, depending on the territory you're looking at between 3 and 8 weeks of backlog on PET scanners at the moment. It's a pretty vibrant time for the GEs and Siemens' of the world. Urology practices are buying heavily into the concept of PET as a must-need instrument just the same way, to some extent, as cardiology did in the past.

So we're going to see more and more PET service provision becomes something embedded in the urology or very much adjunct to a urology practice. And I think 3 to 5 years from now, 25%, 30% of patient volume will really come through directly from -- I hesitate to, from a compliance perspective, use the term self-referral. But that's effectively what it's going to be.

Urologists have seen that this is big. They're the owner of the patient. And so the industry has to pivot to accommodate that. And that's how we think about clinical management very acutely in the next couple of years.

Just from my perspective, it was just last time I had a call with our manager, I'm like, okay, we're going to be scanning all weekend. Like that's a new thing. We're going to set it up, we're going to scan it, we're going to use these two agents. We're going to have it done. And the imagers are also on the NCCN.

And one of the things that we did or one of the things we were pushing for behind -- which worked, was to -- because they wanted to have conventional imaging done prior to PSMA PET because you needed to have a scaffold for that, and we were like get rid of that, right, because you can't scan on Saturday if someone was like, okay, but you have to do a bone scan first or you have to do something else here.

So it was actually -- we're also pushing on the other end to make it really more simple to get to the [ end ] because it helps us as well. It helps the patient care as well because when they are diagnosed, they want to be scanned, they want the scan to be read immediately. And we have to get to that point because there's no other answer then yes, we're going to do it.

So that will cause a redistribution a little bit of scans out further and further out of the urban areas and more rural, which is a part of the Gozellix strategy to alleviate that and redistribute.

From a Gozellix perspective, we have filed for a transitional pass-through, and we plan to hear from them in this quarter as well. So getting ready for that October 1 approval day for that. So that's the expectation. That's what we've done.

So yes. Thank you very much for your questions.

[indiscernible] presentation on 591, and then we'll have some more Q&A and take a break. So thank you. So lots more opportunity for questions Thanks.

So hi, everyone. I don't know if the microphone is working at this one? So thank you, everyone. So it's my pleasure to be with you today to present the therapeutic Telix portfolio. And without waiting, let's deep dive on what I have to present to you today.

So on this slide, you can see that our ambition at Telix is to build a really depth and breadth portfolio for therapy. And you can see that we are focusing our attention on mainly three pillars or disease areas I'm used to say.

So the first one, as you can see, it's urology with the focus on prostate and kidney, and it resonates with what you heard from my colleagues a few minutes ago. The second one will be for brain and rare cancers, but mainly for glioblastoma. And the second one will be the pan tumor -- the third one, so we will be the pan tumor with two targets that we have really notified, the TLX400 and the TLX252, but I will come back on that in a minute.

So if you agree, let's focus on the upper part of the slide with the late-stage assets. And you recognize the well-known [ Lu-TLX591 ], which is currently in the Phase III trial, named ProstACT GLOBAL, where we try to treat the mCRPC patients.

We have also the lutetium-250 compound that is dedicated for the treatment of clear cell renal cell carcinoma. And the third one is the iodine-TLX101 with the potential to be the first radiotherapy for the treatment of refractory glioblastoma.

You can see that for all the diseases, we have treatments at different stages of development. And the bottom part of the slide represent the next-generation platform, where we have all our alpha programs. And you can see the variety of alpha programs with the actinium or astatine that's that we tried to develop for the life cycle management of these treatments in these precise disease areas.

This slide illustrates the clinical and the commercial interest of the diagnostic strategy that we develop within Telix. You understood that we have our Precision Medicine compounds. And for each of the disease I previously mentioned, you can see our Precision Medicine compounds is associated with at least two therapeutic compounds that we want to develop.

So that's really the strategy that we have. And you can understand that the diagnostic and the Precision Medicine compounds will provide near-term revenue for -- to fuel, if I can say like that, the development of our therapeutic compounds.

And more than ever, you can see that the total addressable market of this disease area from a therapeutic standpoint is very significant, and it's paving the way for the future of Telix in terms of potential revenues.

The next two slides are there to illustrate the very amazing and very complete portfolio that we have. I do my math properly, you will see here the late-stage assets. And on the next slide, it's the early-stage, early programs. We have more than 10 compounds under development.

I mean this business of radiopharma since 15 years now, and I can tell you that we are probably the unique company, the radiopharmaceutical company with 10 compounds under development currently. So we have here the early programs. That's the next generation with the alpha I was just mentioning, which are entering in clinics for all of them.

And I even do not add to this pipeline with the recent acquisition of ImaginAb, where we have two additional lead compounds in preclinical, namely the DLL3 and the Integrin avß6, which are already well known from the medical community because there are ADCs under development currently. So now we envisage to put some radioactive isotopes on these targets, and we will develop them in the future. So the road is long in front of us, but a fascinating portfolio within Telix.

So here, it's what are the catalysts for the year 2025. So we already disclosed the IPAX-Linz data for the 101, and the professor of the group will come back on that in a minute with some more granularity details.

We have also filed the ethics submission for the pivotal trial, for the 101 trial in Australia. We expect by midyear, end of summer, the results of the Part 1, ProstACT GLOBAL Phase III trial with the safety and dosimetry imagery data. And by end of the year, we also plan to launch the 250 pivotal study trial for the 250.

In the middle of the slide, you see that we have also some next-generation compound. The TLX090, I did not mention that, but it's the perfect companion product for the urology franchise because here, we are we are targeting the bone pain for the patients, which are really on the salvage therapy, and we are initiating the IND this summer for a Phase I study.

And the 252 and 592, which are the alpha programs in the life cycle management of our urology portfolio, will be the first alpha therapy that we do plan to initiate by this year. So all are the catalysts that we have this year.

And let me hand over to my colleague David, our Chief Medical Officer, that will go deeper on the urology portfolio and more precisely on the 591 to start with. Thank you.

Well, thank you, Richard. I think that's -- I mean there's a clear level of passion that I think you exhibit for your portfolio in the theranostics business.

But let's now turn our attention a bit more specifically to our prostate cancer program, which I'm going to introduce quite briefly before I pass on to one of the -- truly the leading contributors to this field. I think, over the last decade, he also coincidentally serves as our co-principal investigator on our Phase III prostate global study, and that's none other than Professor Oliver Sartor.

But before I hand over to Professor Sartor, I would really like to make, I think, a very important observation, and that is that the identification of the PSMA target itself as well as the development of agents against this target really have, as you've seen, I think, in some of the earlier content; actually transform the way that we manage and look after patients with prostate cancer over the last 5 or so years.

And while the currently approved peptide-based approach is important and Professor Sartor had a pivotal role in bringing that to patients in the United States and now in other parts of the world, Telix's lutetium TLX 591 asset is indeed a highly differentiated approach. And that aims to differentiate itself and overcome some of the limitations that we know exist with small molecule and peptide-based approaches.

And I think it's worth covering these in a little bit of detail, these differentiations really can be classified across four key domains.

So the first of those is that the mechanism of action characterized by an antibody really sees it internalize into the prostate cancer cell, where it's prolonged retention at the target and its functional selectivity for that target is markedly different from a peptide or small molecule. So it's very prolonged and sustained at the target site.

Secondly, from earlier trials, Phase I and II trials, there has been some quite prolonged survivals demonstrated. So this asset has clearly earned its right to be examined in more detail in the Phase III setting.

Thirdly, the patient-friendly simple dosing regimen comprises two fractions over 2 weeks, which really facilitates the use of this agent in combination rather than instead of the available standard-of-care agents.

And then finally, an antibody by virtue of its immunospecificity has very limited off-target effects on the salivary glands and the [ tear ] glands, which don't sound major, but they do have a major impost on the quality of life of patients, particularly as we see these agents become used in an earlier disease setting. So as well as that, this asset has a very predictable toxicity profile as well.

So I think most in the audience are highly familiar with our prostate global Phase III trial, this is our Phase III of lutetium TLX591, which is currently enrolling patients. And it's actually very close to completing dosing of patients in Part 1.

Part 1, as you can see, is more on the left side of the schema, is the safety and dosimetry lead-in in 30 patients. And as you can see, Part 1 is evaluating the safety of TLX591 together in combination with the androgen receptor pathway inhibitors, abiraterone or enzalutamide or the quite widely used chemotherapy agent docetaxel as well as evaluating the tumor and normal tissue dosimetry.

Docetaxel eventually, ultimately is offered to a patient typically in the United States, but very widely used, particularly in other parts of the world, Germany, Europe, Japan and other parts where we are conducting the study.

So what does success look like for this trial in Part 1? Well, ultimately, success for those 30 patients would be really a safety profile that confirms the feasibility of administering 591 together with this broad range of standard-of-care agents.

That really is consistent with the extensive data that we've got, that's been well established in terms of its safety profile from prior studies. And the same outcome really for dosimetry, which would enable us to advance the asset the randomized treatment expansion, which is the really -- that's the main game of this study once we finish the Part 1.

So this study currently has a very significant investigator interest, and I think the momentum is rapidly building in this trial. And it's important to note, while we have to pause when we are enrolling patients in the United States at the end of Part 1 and take the data back to the FDA, we have the permission to seamlessly proceed into Part 2 in other sites, where we are running this trial outside of the United States.

So that's a brief introduction, and I have now truly the great pleasure in handing over to Professor Oliver Sartor. So I'd like to invite you up here, Dr. Sartor.

Thank you. A pleasure to be here. Chris, in particular, I'd like to thank you for your support over the years and what you're doing. Chris is a pretty remarkable entrepreneur. He started with not much, and now he's got something. So well done Chris.

By the way, I have a new title. I'm no longer at Mayo Clinic. I just made up my new title, by the way, I'm Director of the Transformational Prostate Cancer Research at LCMC hospitals. I like the transformational part and that's we hope to do it down to New Orleans, be heading down there next week.

I think most of you are aware of the differences between small molecules and the antibodies. Many of you know that I've been very involved with the small molecules, they're good. There's an opportunity to change practice, and there's already been FDA approvals, and I think there's going to be more to come.

But there's some shortcomings as well. And here, we're going to be talking about some of the opportunities that I think are present with the antibody. TLX591 is by far the furthest along. There are other antibodies out there, but they're considerably behind. I might point out the one from Bayer. By the way, it was a failed attempt with the thorium-227. They're trying again, but they are behind where Chris is, for sure.

One of the real advantages of the antibody is the two doses, which are pretty simple, just 2 weeks apart. And it turns out that they are going to be retained, circulate for a while. Really, really good tumor uptake. We're going to look at some of the tumor uptake.

One of the cool things about lutetium is you can use spec scanning to be able to see exactly where the isotope is, and you can see the localization, no salivary, no kidney. You're going to be able to see it in the tumor.

You'll see hepatic uptake. Initially, when I worked at it, by the way, on the hepatic uptake, I said, well, goodness, that could be dangerous. But it's not. And it turns out there are very few in the way of liver function tests that are going to be problematic.

When we move to thinking about the clearance, and I'll just talk a little bit about this now and come back to it later. The limitation on the small molecule has been built around these two organs, salivary and kidney. The salivary toxicity on the small molecules is probably rate limiting. When you go to actinium, you'll see that to a much greater extent, not a huge problem with lutetium, but the limitation on the dose on lutetium with a small molecule is related to the renal dosimetry.

The FDA has strong dissymmetry guidelines. Again, I'll come back to this. Typically, around 23 gray. And if you look at, say, the SPLASH trial, which you may or may not know, it was 6.8 gigabecquerel [ Q 6 ] weeks, and that was really too low, it was about the renal dosimetry. If you look at the 7.4 gigabecs on the small molecule [ Q 6 ] that is built in to the renal limits.

It's not due to the DLTs that are observed. If you look at the DLT that were done in terms of the dose escalations, the small molecule, it's not about the DLTs at all. It's about the renal dosimetry limits. And the antibody is going to avoid that problem. And that's going to have another potential DLT. But nevertheless, the renal dosimetry problem is solved with the antibody.

So when we look at on the left side, we're going to see the basically, the PSMA-617 RLT, [ 6 ] infusion over 30 weeks, a little bit longer to administer. You do have some dry mouth that is present probably in the majority of patients in the PSMA-4 setting, which is the texane-naive setting, castrate resistant. You begin to see that, that's over 50%. It can be a problem in some patients. It is a persistent problem in a few. It's a relatively common complaint. And this is an advantage of the antibody, which simply doesn't have it.

The renal toxicity issue, it's not so much renal toxicity is the renal dosimetry limits sort of problem. And I think there is an opportunity to improve efficacy, tolerability and dosing regimen. And that's where the TLX591 comes in. You have a 2-dose regimen that's 14 days apart. You have the hepatic clearance, which really solves dosimetric problems, and you also avoid the salI'veary uptake. So that's kind of where the opportunity lies with this molecule.

Now on the left-hand side, I think we're all pretty familiar with the landscape and the evolving landscape in prostate cancer, by the way. If you were at ASCO, one of the best things at ASCO for me was not presented at ASCO, but it was the PSMA-617 reporting on the metastatic castrate-sensitive space and the RPFS positive OS trend positive more analysis to be needed in that trial, but it's likely to lead to an FDA approval upfront.

If you look at TLX591, the ProstACT GLOBAL, which was presented a little bit earlier, is the Phase III that has the lead in. And currently, they're in the lead-in phase. I'll try to get some up-to-date information. There were three components to the lead in, as discussed with the FDA.

Number 1 was the abiraterone combo, #2 is the enzalutamide combo. And the third was the sequential use of docetaxel. So the abiraterone is already fully accrued. Enzalutamide is very, very close to being accrued. And there a few more. I think there are 6 more to go on the docetaxel, it's given in sequence.

One of the things I like about this trial is that you integrate the standard of care in combination unlike the PSMA-4 trial, which was a monotherapy with the PSMA-617. To emphasize the ProstACT SELECT and that is the data that has been accumulated predominantly coming out of the Cornell Group and more, there is an interest in these outcomes, and you'll see that the survival outcomes have been outstanding, but of course, that needs to be verified in the Phase III trial.

This is the survival outcomes that are outstanding. Again, this was with the two doses of the antibody. And there were some sort of eye-popping overall survivals 42.3 months supported for castrate-resistant disease, and that's like rather phenomenal. These are patients who had pretty high burden. And there does seem to be this survival benefit that attracts people's attention, certainly attract my attention. This was presented by Scott Tagawa. Scott Tagawa, by the way, Cornell's close collaborator, close friend, and we've worked together for many years. This data is very reliable. I trust Scott completely.

This is the distribution, and I think it's a little bit interesting. On the left-hand side, you'll see a PET scan, typical PSMA-11 Gallium PET. You'll see the salivary uptake. You'll see the renal uptake. And of course, you'll see the tumor. On the right-hand side in the box, you'll begin to see SPECT scanning. So this is taking advantage of the lutetium, which has the ability to be imaged with SPECT. And you'll see 4 hours, 24 hours and then 4, 7 to 13 days. When you see the injection, you'll see the vasculature because of the antibody that's going to strike in the vasculature. You don't see the salivaries because it didn't hit the salivaries. So it's very interesting. There's seemingly a barrier for the monoclonal that you don't see with a small molecule. So that barrier of the salivary toxicity and then you begin to look at the kidneys. You don't see the kidney, you see that you see the liver, you can see the spleen.

When you carry it through over 24 for 7 and 13 days, you begin to see the remarkable retention within the tumor. And that also caught my attention when I sort looking at these scans. That retention within the tumor is really, really, really good. And you, again, don't see the salivaries, you don't see the kidneys. You don't see anything in the bladder, but you do see the liver. When I first saw the liver, like I said, I had kind of alarm bells go off but it turns out there's really no liver toxicity and look at the dosimetry limits. It's nowhere near the dosimetry limits within the liver.

This is the 617 over 5 days. Interestingly, you'll see some gut excretion, and that's something that wasn't necessarily anticipated. If you look carefully at the AEs, you'll see some GI side effects for the smaller molecule. Occasionally, these can be problematic, and it's typically some diarrhea or maybe some abdominal discomfort and kind of leg cramping. We do see that in the clinic. You see the salivary retention, which is, of course, very, very well known. The kidneys do wash out but you're approaching the dosimetry limits, and that's been well shown and well-studied.

This is the safety data from the ProstACT SELECT study. The issues really revolve around the hematologic toxicity. And you can see the anemia that is present but in terms of grade III, grade IV, didn't see it in this study. Lymphopenia, which, by the way, is not really clinically relevant. I mean, we've seen the lymphopenia with a variety of both cytotoxic chemotherapies as well as radioligand therapies. And I'll simply say that if you're looking for consequences of lymphopenia for opportunistic infections, you just don't see it. People have labeled it, by the way, as grade IV implying that it's really dangerous. But to the patient, it's not. And I've treated many, many, many patients and I have never seen any of the pneumocystis or other opportunistic organisms that might accompany lymphopenia.

Neutropenia, you can see is grade IV, only a very small percentage of patients. Neutropenic fever is not a problem. It doesn't particularly last that long when it does occur. So it's a small instance of grade IV. Yes, you can have some grade IIs and IIIs, but clinical consequences from that for the patient are pretty minimal, if not at all.

Thrombocytopenia, you do see some thrombocytopenia in the grade IV, you're probably running about 6% or so. You do get some grade IIs and IIIs. It is relatively predictable, and I'll show that here in a second. You can get some fatigue. You can have a little bit of nausea. You can have some loss of appetite. Probably just due to the circulation and the radioactivity, not completely clear but fatigue does accompany this in some patients.

The dosing regimen kind of covered it before. It's really just 2 weeks between treatment. You get infusion 1, give infusion 2. The infusion goes in over about 5 to 15 minutes, pretty short infusion. This has real advantages compared to some of the RLTs, which are going to be using higher doses of the activity. Here, the actual amount of the radiation administered is much lower than with the typical RLT peptides like 617. You can have a very rapid discharge. You can also turn over your chairs a lot quicker and not occupy the chairs as often. That's advantageous for patients, advantageous for the treating physician.

So there is an assessment typically around day 11, where you're looking at the potential for hematologic AEs, get a blood draw, have the patient come back in. But overall, the burden for the patient in terms of the overall treatment is pretty simplified, and that's a good thing.

This is a predictable and relatively consistent findings from the heme tox. If we're looking at the platelet counts, and you can see that the depth of the platelet decline is going to predict to a significant degree about the duration of the decline. If you're sitting grade 0 to 2, you back of 150,000 pretty quickly in the majority of patients. And that has no consequence. You certainly don't get any bleeding when you're talking about 100,000 platelets. It's just not consequential.

If you end up with a grade 4, you see that there can be a little bit of a delay getting back to kind of 100,000. But I'm unaware of any bleeding that's actually occurred and there have been some platelet transfusions given. I think that's going to be a rare event. I think for those patients who are used to chemotherapy and physicians who are used to chemotherapy, this is going to be pretty well tolerated and not anticipating much in the way of problems. It's going to be easy for both the patient and the physician, at least that's certainly the hope.

This is what I was mentioning about the cumulative actual amount of radioactivity administered. If you're using the PSMA-617, you're talking 200 millicuries 6. So you're talking basically about 1,200 millicuries for the antibody at 76 millicuries is 2. That leads to easier discharge, easier management of the patient who has to worry about sleeping in the same bed with the spouse, being exposed to grandchildren and stuff. The lower dose of radioactivity is going to be a little bit easier on the patient from that perspective, minimal safety requirements. So it's actually a pretty dramatic difference between 152 millicuries as opposed to 1,200 millicuries. And I think that, that could have some advantages as we go forward.

These are the dosimetry thresholds that have been calculated. Let me just kind of take you through this quickly on the right-hand side for the liver thresholds about 32 gray, salivary about 25 and for the kidney, about 23 and bone marrow about 2. These are typically accepted limits by the way. I think we do have to have dotted lines here because they're debatable in their limits. But nevertheless, this is what has been guiding some of the dosing, a fair amount of the dosing throughout the globe. And this sort of dosimetry limit is what basically kills [indiscernible], just kind of putting that out there. That has not been very well discussed because it's presented at ESMO, what, 2 years ago, and it's never been presented since.

The antibody is going to be shown here in the histograms. You're going to be looking on the right-hand side in the tall part of the histogram, that's liver but nowhere near the threshold. Next is spleen, nowhere near the threshold, didn't show the spleen threshold but it's up there. Kidney threshold with a 23 gray, not even close. Lungs, we didn't put it up there, but not even close. Red marrow is 2 gray limit and you're running about half and then everything else is way below. So the bottom line is from the dosimetry estimate perspective, the antibody looks pretty good.

If you look at the small molecule, the salivary is getting right up around the threshold. And particularly, by the way, we're not talking about actinium today, if you're talking about actinium with a small molecule like 617, that where there's going to be trouble.

If you look at the kidneys, and this has been, again, the limitation for some of the dosing that has gone for the PSMA-617, you're approaching the kidney limits when you're given the 200 millicuries times 6, and that's what's prevented people from going higher with the small molecules. The salivaries and the kidneys are the 2 kind of areas of concern. You do end up with more colon radioactivity than expected. But again, AEs there are not so bad. So it's okay.

Questions and answers, and I think we're going to have the panel. Is that how it's going to work? I'm looking for direction.

My name is Robert Burns from H.C. Wainwright. When we think about the competitive landscape here, obviously, most people will point to the convergent therapeutics compound, which is it incorporates actinium-225 and the exact same targeting moiety. So I'm curious where you see the differentiation there, especially when we take into account that the meta-analysis has shown that actinium-22 has produced more efficacious results than lutetium-177 in mCRPC.

I can comment on that. The conversion is probably going to be targeting the post lutetium space. They're working hard to be able to move forward. It turns out that it's creating a little bit of a problem if you haven't started your Phase III at this point. I think one of the things about the Telix molecule, they started the Phase III. These spaces are getting sort of taken up. And it's going to probably end up with some head-to-head trials if you're going to be able to move it up any further.

So the delay, there's always an advantage to the first mover. I think there's an ability for Telix to slip in on the current Phase III. But in the future, those trial designs, control groups are going to change. I don't know if anybody else would like to comment.

Yes. Perhaps I can complete the answer because we -- they are working with the 591 actinium. That's a good thing. But you probably saw in our portfolio that we are also anticipating that with the 592. We have customized the development of this antibody to compare very typical specificities in terms of pharmacokinetics, which will fit perfectly with the alpha therapies, which is the actinium that we will attach to this compound.

So they are paving the way. They have to demonstrate the efficacy but I'm really confident that we have also a game changer with the 592 actinium. And both lutetium and actinium will coexist in the treatment algorithm, I think, in the future, so.

Andy Hsieh at William Blair. Two questions really about the cumulative dose administered versus cumulative dose absorbed. So you kind of quantify the two metrics, almost 10x higher, right, for the small molecule. I'm just curious, obviously, with data coming with symmetry, you might get that with an antibody. But how correlative is that with the absorbed dose? And also the cumulative dose given? And how does that -- the implications on the clinical front?

I love your question. I don't know the answer, maybe I'll see if somebody else can answer it. But you end up with a really remarkable retention time. Please remember that the absorbed dose is the area under the curve. And so the curve is going to be a little bit different here. And the key value to me is a therapeutic ratio. And you see the retention, you see the SPECT scans, and you do have remarkable retention here. I'm not sure if that's the exact absorbed dose. I don't know if you could -- anybody can answer that?

Yes. Andy, great question. Nice to see you again. So obviously, as I presented on ProstACT Global Part 1 does have dosimetry, not just what Professor Sartor showed, which was the radiation of absorbed dose delivered to the nontarget vital tissues but also, obviously, the tumor compartment itself. And that will be part of the data that we'll have very shortly. So that's a very interesting piece of the data. I think it's a very important one, together with the safety profile, of course, with 3 different combinations. So that will be presented. Yes.

So the second question has to do with the RCC program 250. Very exciting second program going into the Phase III or pivotal studies I'm curious about the potential for an accelerated approval there. There's one example before the lenvatinib/everolimus Phase II approval there? I'm just curious about how you're thinking about the kind of potential speeding of the development path there.

Yes. It's true everolimus obtained an accelerated review process but it was a long time ago. Now the FDA is a little bit more skeptical on accelerating review process on that. But let's see, we have to pave the way with the 250 in renal cell carcinoma. Zircaix is explaining the expression of the C9 in ccRCC. I think we all agreed that it's a game changer. For the therapy, we have to run the Phase III trial and on due time going to the FDA. That's what I can say.

Brandon Carney from B.Riley Securities. Just wanted to ask on the 23 gray limit to the kidney. I think you mentioned that that's a controversial limit. Wondering what you think the possibility of extending beyond that in near-term scenario?

This has been a very active discussion. I don't know if you're aware, there was an FA, SNMMI meeting last May. You're -- were you there? No, we're there. But it was -- a lot of it focused on this. So let's talk about 23 gray. Where did it come from? What's the current status and what might change? Number one. It came from the use of EBRT, and the risk is 5% of renal failure at 5 years, which is remarkably low and irrelevant for many of the patients with advanced cancer because they don't live for 5 years. This VISION trial, where we have good data, 15 months, even PSMA-4, which is taxane naive, 24 month. So the 23 gray limit begins to crumble when you're treating advanced cancer patients, and that's one of the strongest arguments against it.

The FDA has a couple of divisions. One division is the one that everybody is familiar with every day, oncology, Rich Pazdur on down, okay? They're pretty reasonable people. But there's another division called DIRM, D-I-R-M, division for investigational radiation medicine. They're filled with people who believe that they can calculate efficacy and calculate toxicity. And they have been imposing some limitations on the entire field that, quite frankly, I don't think are reasonable. There's a debate going on in part, and this is interesting and this is a personal interpretation. I'm not sure I want to be quoted on this, so don't quote me but the oncology division and the DIRM division are not always seeing things eye to eye.

But because all the isotopes are passing through DIRM, there's a sign-off there. and the limitation is beginning to get some potential relaxation but it's still a bit of a problem. So the calculators at DIRM are imposing limitations that extend beyond the clinical DLTs.

Now let's talk about how that could be reasonable. I'm sorry, I'm giving you a long answer because it's really complicated. It's a great question and a very important question. The DLTs are typically observed over 42 days, 49 days, 56 days, a pretty brief period of time. The problem what people are fearing is that there could be deleterious effects long term with radionuclides. 5, 6 years down the line, particularly if you're looking at actinium, let's imagine you're going to be treating neuroendocrine patients, SSTR2s, actiniums. Guess what? This could be a real problem.

And that risk is a bit unknown, but the longer the patient lives, the more likely it is to be problematic. And that's where the 23 gray and it could be more of an issue. And by the way, nobody knows how to really equate particles like betas and alphas as compared to EBRT and the EBRT extrapolations are probably not so great. That's a long answer. Hopefully, I got to the heart of your question.

We're going to take one last question here.

David Nierengarten, Wedbush Securities. Just kind of following that and another question on 591. You mentioned the PSMA study. Is there -- we've seen taxanes come and go in earlier lines and later lines. Is there a level of toxicity, a level of efficacy thought that would really change practice to incorporate PSMA 617 into frontline use? Or do you think it's more likely still going to be relegated a little bit later just because of the toxicity profile and cumulative radiation exposure potential in the longer-lived patients or patients with longer likely lifespans?

Yes. So you have a couple of interesting points rolled into there. If you move the 617 earlier, and I think it's likely to go earlier, there'll be many questions about the tolerability of the chemotherapy down the line. And I can say that I've looked at this to the very best of my abilities. And I can say, so far, there doesn't appear to be much in the way of chemotherapy distinctions like in the randomized trial, PSMA4, we do have a follow-up. We can look at it and it appears to be equal between the 2 arms. We can't really pick it out but it may be a little shortened in duration.

One of the things I do like about the ProstAct GLOBAL trial is you're building in the docetaxel to both arms. By the way, one of the things that the FDA has moved away from is using hormones only as PSMA-4 did in the control arm. So when you put the docetaxel in the control arm, you introduce conflicting and potentially mitigating factor because typically, the RPFS and the OS in the docetaxel treated patients is going to be better than the ARPI, right? Okay.

Here, you bring ARPI into the isotopic arm and you bring the docetaxel into the isotopic arm. Now is the dose going to be able to be delivered in the same way, same effectiveness same duration? I think there are questions. But for the hormones, there's not a question. And I do believe that there is potential synergy between the hormonal even in the second-line setting of RP plus the isotope as compared to the isotope alone. So you get a little extra boost in my opinion. You probably saw the ENZA-p trial if you follow the space. Yes. So there, there was an unequivocal benefit of the combination of enzalutamide and the PSMA-617.

And I think you'll be able to take advantage of some of that synergy here, which was missing in the PSMA-4 trial. By the way, why was it missing in the PSMA-4 trial? The original design was very similar to the VISION trial brought forward with the standard of care being able to include ARPI. FDA nixed it. They said no. So it was monotherapy as a result of the FDA feedback. Here, the FDA feedback has allowed it. I think it will be advantageous for the trial design.

Thank you. So we're just going to take...

One more thing I'll say. Really, really good questions. These are thoughtful questions.

Appreciate it. We're going to take a very quick break, 5 minutes. So if I can have you back in here at 10:45, just a chance to grab a coffee, and we'll continue on with the presentation.

[Break]

Take your seats, please. Dr. Liu. I hope that biopsy needles safely stashed somewhere. Yes. Good. All right. Well, I think we're into the second half here, Ky.

I have the real pleasure of moving into the. There was actually a very good question about the alpha program. It was just here, I think. And the comparison with Convergent, there are alpha programs. I think the Telix alpha program is a very exciting program that I'm really looking forward to talking to you about briefly. This is our TLX592 asset in prostate cancer, which is an actinium-225 labeled engineered antibody. So it is a different antibody from the father antibody, TLX591, which in its most simple terms, it's very similar to TLX591, that antibody, except that it possesses pharmacokinetics and a biodistribution patent that clears from the circulation faster.

So what that really means is that there's fewer alpha decay events that occur in the blood circulation, while the modified antibody that's been reengineered retains a very similar tumor targeting and retention profile to the father antibody TLX591. So if we look at the 2 main difference between 592 and 591, I think it's important to sort of have an appreciation for these.

So the first of the difference is that the 592 antibody has been FC engineered. So that means that it rapidly clears faster from the circulation. And because of the choice of payload for this drug candidate, what we want is to remove the excess radiation out of the circulation reasonably quickly, while also balancing and ensuring that there's enough circulation time for it to target, localize and internalize the payload into the prostate cancer cells. So that's the first difference.

The second difference, of course, is an obvious one, and that is that the payload itself is different. This asset delivers actinium-225 instead of lutetium 177. So actinium is an alpha emitter that has a very potent but high energy localized deposition of radiation. It really only -- its path length is really only a few cells deep unlike a beta emission, which goes millimeters and possibly in a higher energy beta like atrium, it might go over a centimeter in distance.

So this asset delivers actinium instead of lutetium. And this may lend itself to being more suitable for treating earlier-stage prostate cancer in men with a lower disease burden or disease volume. So in general, beta emitters, we believe, like lutetium, or yttrium-90 or iodine-131 are ideal for effectively irradiating larger bulkier tumors, whereas alphas more -- lend themselves to be more suitable for localized small volume disease.

So TLX591, it is still hepatically cleared. Professor Sartor showed the profile for lutetium 591 but 592 is still hepatically cleared. And this is very important because alpha emitters should be really kept away from the kidneys and not filtered or extracted from the circulation via urinary excretion by the kidneys into the bladder and then out of the body that way. The liver, as we saw in those biohistograms is a much more radiation-resistant organ.

So I recently -- earlier this year, January, I had the pleasure of the honor of actually reporting the results from our earlier CUPID study. This is a Phase I study presented at this ASCO GU, which evaluated the biodistribution and the dose to the organs of the copper-64 labeled imaging version. So this is the imaging version of this asset at escalating mass doses that range from 2 milligrams up to 20 milligrams. And this study enrolled 11 patients. It was a Phase I trial with advanced prostate cancer comprising 4 groups.

The patients in groups 1 to 3 had low volume disease, which we defined as 5 or fewer lesions or really oligometastatic disease. And group 4 had higher tumor burden, which we defined as having 10 or more metastatic lesions. And what this study was able to demonstrate was that in terms of pharmacokinetics of 592, the agent clears from the blood much more rapidly than 591. And to put some numbers to it, the blood clearance half-life of around 2 hours -- sorry, 20 hours accompanied this asset compared to about 34 hours for 591. But it otherwise had a very similar biodistribution pattern.

And then 592's biological half-life in the blood showed a clear mass dose relationship. So the more antibody mass that was present, the longer -- the more it was pushed out of the liver, which is the clearance organ and its residence time in the circulation was higher. So if you look at the images in the panel on the right, this is one of the representative patients from the CUPID study. This is a patient who on the left-hand panel of those images, obviously has a prostate cancer that is spread to his skeleton. This is lit up using Illuccix, a Gallium-68 PSMA PET in his lumbar -- L3 lumbar vertebral body. That's in the lower part of the back. And then on the right-hand panel, you can see the same targeting of this tumor deposit with TLX592, albeit in this case, the antibody has been labeled with Copper 64, so you can visualize where the antibody has gone. You can't do that to the same extent with actinium.

So to conclude, really, the CUPID study, what do you take from this study? The CUPID study ultimately constitutes a successful proof of concept of this asset, and we really look forward to moving into a Phase I first-in-human study with the actinium version of TLX592 in the second half of this year.

So with that quick fly through, I'll now like to invite Pamela up to move into the 090 asset. So over to you.

Thank you, David. All right. Thank you. So I'm Pamela Habib, Chief Medical Officer for Therapeutics, and I'll be talking about TLX090 and TLX250 today.

So I'll start with TLX090. This is our Samarium-153 labeled DOTMP agent. And this is being developed to treat the pain palliation in patients that have osteoblastic metastatic disease. This fits in nicely with our urologic platform because frequently, the patients that have osteoblastic metastatic disease have prostate cancer. Another common patient population that presents with osteoblastic metastatic disease is the breast cancer patient population. And we acquired this molecule from another company, and so it's a proven isotope platform, and we've now attached a novel chelator to the isotope. And this is expected to lower the bone marrow dose and to be -- have increased tolerability for the patients.

And as I mentioned, we're developing it for pain palliation. But there is a potential for also treatment of the osteoblastic metastasis in the future development pathway and also for multiple doses. Currently, we're developing this as a single-dose agent, but there is a potential in the future for multiple dose regimens as well.

We have early studies with this agent where we have seen improved quality of life in patients with diffuse metastatic disease, and I'll talk about that data a little bit later on. And currently, we're in the process of designing a Phase I bridging study. So as I mentioned, we acquired this asset from before [indiscernible] Phase I bridging study, which we feel will accelerate our path to a registrational trial in the future. We're planning to commence this Phase I bridging study later this year.

On the right-hand side of the slide, you can see an image, and these are the types of images as radiologists that we love to see. This is a patient with metastatic prostate cancer, and he received Samarium therapy for his pain. And as you can see, his entire left side, which is on the image -- the right side of the image but it's the patient's left pelvis and his left femur are lighting up more than the other side. And this gives us confidence that the Samarium that was injected into the blood has made its way to the lesions in the pelvis that we were trying to treat.

There is a significant unmet need in these patients that have diffuse metastatic disease. Any clinician that has spoken with a patient who has mets all over his body will tell you these patients are in tremendous pain. They wake up with pain, they walk around with pain, they're sitting in a chair and they just feel pain everywhere. There are treatment options but they're not -- there's definitely room for improvement. There are opioids but as we all know, there is a potential for dependency with opioids. There's steroid therapy, there are bisphosphonates but they all come with their own side effects and they don't offer complete relief. So there's definitely room for improvement.

EBRT or external beam radiation therapy is also an option, but that's difficult for logistically and in patients with metastatic disease all over the body, it's a little bit less suited for that. It's more suited for limited numbers of lesions. 80% to 90% of patients with metastatic prostate cancer will eventually have a bone lesion. Similarly, with breast cancer, 65% to 75% of metastatic patients will eventually have a bone lesion. And in terms of the immediate market opportunity, there are about 30,000 patients that have late-line prostate cancer or Stage IV breast cancer that are expected to progress.

I mentioned that we have some data from previous studies. And so in our earlier Phase I studies, we saw that all patients experienced a greater than 20% reduction in their pain scores within 6 weeks. They also anecdotally talked about just an overall improvement in the ability to move around and to walk around because they're feeling reduced pain. And there's also an opportunity to decrease the dependency on opioid or other analgesic use.

In terms of the safety profile, we did not see any dose-limiting toxicities in any of the patients. The hematologic toxicities that we saw were mild and transient, and we did not see any clinically significant impact on liver function or kidney function. Of the two adverse events that we saw, they were both deemed to be isolated events. One was thrombocytopenia in a patient that had metastatic disease throughout the entire skeleton. And the second patient who developed changes in his EKG had pre-existing cardiac abnormalities.

So that brings me to the Phase I bridging study that I mentioned previously, our SOLACE trial. So this is being designed as a two-part study where Part A will be the dose escalation phase, and we will have three different activity levels that we will recruit in a parallel fashion. And then Part B will be the dose expansion where we will select two of the doses from Part A and then expand on those with the primary endpoint of being determining the optimal biologic dose, depending on the safety profile as well as the reduction in pain score.

The 16-week time frame, we feel will allow an opportunity for a relatively shorter clinical trial compared to the longer trials that look at overall survival or PFS in terms of efficacy because we're expecting to see the reduction in pain to develop within 16 weeks after receiving the injection.

Now I'll move on to TLX250. TLX250 is lutetium-labeled girentuximab, which is a CA9 targeting agent, as you heard mentioned previously as well. And this is a validated target. We already know that it's expressed in greater than 90% of clear cell renal cell carcinoma. You heard the ZIRCON trial mentioned this morning. And it's also been shown to be expressed in a number of different solid tumors in addition to clear cell renal cell carcinoma.

We have Phase I and Phase II studies that have already demonstrated durable disease control with this agent as a monotherapy with a manageable safety profile, and I'll talk about that a little bit on the next slide. And there is, in general, a high unmet need in this advanced patient population in the third and fourth line.

On the right-hand side, you can see images again, and this is a patient with metastatic advanced renal cell carcinoma. And the top row shows the initial images that they had. So they received a zirconium-labeled girentuximab scan. You can see intense activity in the sacrum where there was a metastatic lesion. And after three cycles of therapy with lutetium girentuximab, you can see on the bottom row that the amount of activity in that sacral lesion has significantly decreased, again, giving us confidence that the injected therapy has made its way to the bone lesion.

The earlier studies that I mentioned, so there's a Phase I and a Phase II trial that were performed with this agent as a monotherapy. The Phase I study was a dose escalation study that determined the maximum tolerated dose after evaluating this in 23 patients who had advanced clear cell renal cell carcinoma. The Phase II study expanded on this and dosed an additional 14 patients at the maximum tolerated dose.

In all patients, we saw a favorable safety profile, and we saw the potential to stabilize metastatic disease in this advanced patient population with monotherapy. And in this patient population, which has rapidly progressive disease, even disease [indiscernible] positive outcome.

The disease control rate we saw in the Phase I trial was 74%, and we saw a median PFS of 8.1 months in this patient population who had a different pretreatment profile, but the results are still very encouraging.

On the right-hand side, this is a patient who has diffuse metastatic disease from clear cell renal cell carcinoma. They received lutetium girentuximab. And on the SPECT that was performed after the therapy, you can see numerous metastatic lesions throughout the body in the brain, in the chest, in the abdomen, all lighting up, all giving us confidence that the therapy made it to these lesions.

This slide shows the overall complexity of the treatment pathway for these patients. And we wanted to really look at this in detail and determine where we want to focus our efforts in our development of this compound. So when a patient first presents, if they have localized disease, they may only get surgery at that time, and they may not need any type of medication. However, if they have intermediate or poor risk or they recur, that's when they start to receive different types of medications.

In the first line, that may be an immunotherapy. such as an immune checkpoint inhibitor. This may also be a tyrosine kinase inhibitor or it may be a combination of the two, or perhaps two different immune checkpoint inhibitors.

Once they get into second line and beyond, the treatment options become very limited. So although there are some newer agents, there's belzutifan, there's everolimus and different physicians try different combinations of therapies, we really haven't seen significant overall survival improvement in the second line and beyond. And that's really why we are focusing our development in two different areas.

So first, I'll talk about on the next slide in detail of our trials. But because there's such an interest in combination therapy in first and second line, we are focusing on a number of trials looking at various combinations of TLX250 and other classes of drugs. But then we're also looking at the third line beyond because these patients really have no other option. They're very sick. There are no treatments that are consistently showing a positive benefit. And so we are focusing our pivotal trial in this monotherapy for advanced third- and fourth-line patients with clear cell renal cell carcinoma.

This is an overview of the trials that we currently have exploring TLX250. So I mentioned the combination therapies. We have STARLITE-1, which is currently enrolling patients. This is looking at treatment-naive patients who present with advanced disease. And the patients are receiving TLX250 in combination with an immune checkpoint inhibitor, nivolumab, and a tyrosine kinase inhibitor, cabozantinib.

STARLITE-2 is also enrolling patients. This is looking at a more advanced patient population. So these patients have already received immune checkpoint inhibitor, and now they are presenting with disease progression. We've already determined the maximum tolerated dose in this trial, and it is currently enrolling an expansion cohort at this maximum tolerated dose.

STARSTRUCK is another combination trial that we have that is enrolling patients. So this is looking at not only clear cell renal cell carcinoma, but any solid tumor that expresses CA9, and this is treating with TLX250 in combination with peposertib, which is a DNA damage repair inhibitor.

And then finally, the pivotal study, which I mentioned previously. So we are focusing on advanced late-stage third and fourth line beyond patients. This study is going to be a monotherapy, and it is currently being designed, and we are planning to commence it later on this year.

That rounds out our urology portfolio. So I will now hand it back to David Cade. Thank you.

Thanks, Pamela.

So nice to be back up here. I think it's my third time. This is the type of asset that as an industry physician is critically important. And this is where, as an industry physician, on behalf of my colleagues, I feel that we have the potential to make major inroads into a malignancy that's somewhat catastrophic in its diagnosis. And Dr. de Groot is going to go into the history of this disease and more importantly, the history of the development of assets for this disease, and there's not a lot of history to tell, I think, as we'll see a bit later on.

So when you've got an asset like this that's showing promise, it really is a very sort of exciting period of time in what we do.

So I'm going to start and again introduce our neuro-oncology program before handing over to Dr. John de Groot, who will delve into the program in more detail. Dr. de Groot has come across to New York from University of California, San Francisco.

So this is our TLX101 asset, which is an iodine-131 labeled small molecule. That's a very important point. I think Chris talked earlier about being agnostic to isotopes and to the delivery vector. But that's important because it's a small molecule and therefore, able to cross the blood-brain barrier and therefore, then become able to target the L-type amino acid transporter, which we know is LAT1.

So this is a very well-validated target that's highly expressed in malignancies of the central nervous system, including glioblastoma. And while I'll go into the clinical studies that have been undertaken with this asset in a moment, it's important to note that its safety profile and its tolerability when administered in combination with conventional external beam radiation therapy has been demonstrated as has encouraging preliminary efficacy results, including quite extended survival durations in prior studies.

So given the absence of effective options for glioblastoma, we are very pleased that this agent has been granted an orphan drug designation, both in the United States and in Europe for the treatment of gliomas.

Our initial focus with TLX101 is going to be in glioblastoma, which is the most common and aggressive form of primary brain cancer with approaching almost 15,000 new diagnoses made in the United States each year. And if we look at -- I'll try to simplify it for you, but if we look at the flow diagram on the right, of those patients diagnosed with glioblastoma. So if we say there's 100 patients diagnosed, about 90 of those 100 will be well enough and will be willing to undergo initial first-line treatment, which comprises maximal surgical resection followed by adjuvant chemo radiotherapy. And that's very, very well accepted and very conventional.

But what then typically happens to those 90 initial patients that then get treated is that on average, after an lapse period of 7 or 8 months, 90% of those patients will experience disease recurrence. So at this point, really, there's no settled upon established second-line treatment that we would offer universally.

And if we look at the NCCN Guidelines, it tells you the whole story. Our clinical trial is a recommended option for treating these patients with recurrent disease.

And so we see that while the 5-year survival of patients with glioblastoma remains stubbornly stuck at just under 5%, so 5-year survival under 5%, a key challenge for potential new therapies that we might want to bring to these patients is that crossing the blood-brain barrier is a challenge. And so it limits the sort of the pool of potential systemic options that we might want to deploy in these patients.

This slide, I think, really nicely summarizes the development pathway for TLX101, both prior and future planned. And while I won't go into too much detail as Dr. de Groot will discuss the clinical trial results in more detail in his session, there are two key points, I think, that are important to take away from this slide.

So firstly, the data from prior studies, IPAX-1 and IPAX-Linz in the recurrent disease setting demonstrated an acceptable safety profile as well as really quite encouraging overall survival durations, both from the time of initial or first diagnosis as well as from the time from initiation of treatment. And so these range in the range of 12 to 13 months and 23 to 32 months, respectively.

And then the second thing to take away from this is that we have a pivotal registration-enabling study for this asset, which we call IPAX-BrIGHT, and that study is expected to open for patient enrollment in the second half of this year. And Dr. de Groot is going to go into the study design in a bit more detail shortly.

And then finally, turning to our targeted alpha approach in neuro-oncology. There are two very important takeaways from this slide. And I think the first of those is that TLX102 uses an identical targeting vector as TLX101, but it's labeled with astatine-211, which is a short half-life alpha emitter. And I described earlier the key properties of alpha emitters, high energy, very short path length. And which may help overcome some of the radiation resistance that we commonly see in cancers of the central nervous system.

And we believe the combination of TLX101 with its longer beta path length, iodine-131, radionuclide may be well suited for patients with larger tumors, while TLX102 may be well suited to patients with smaller and more diffuse disease with that short path length and high energy deposition of astatine-211 is more ideal.

And then secondly, the key takeaway here is that a recent case report from our collaborators at the University of Medical Center of Utrecht, which is in the Netherlands, published, I think, a very important piece of research. It was a single patient case study, but they are continuing to examine this approach.

This patient received TLX101 via intra-arterial administration. So not systemic IV administration, which is the way radiopharmaceuticals are typically given, but by the -- it was the middle cerebral artery in this instance, administered via a temporary catheter. And this represented proof of concept that this administration method is safe and it's feasible and could potentially deliver a much higher radiation dose to the tumor. So we do intend to further those studies and evaluate this administration approach in a first-in-human study in glioblastoma.

So with that brief introduction, I have great pleasure in welcoming to the podium here, Dr. John de Groot. Over to you.